| Endometrium | |
|---|---|
.svg) Uterus andfallopian tubes (uterine tubes). (Endometrium labeled at center right.) | |
 Endometrium in the proliferative phase | |
| Details | |
| Part of | Uterus |
| Identifiers | |
| Latin | tunica mucosa uteri |
| MeSH | D004717 |
| TA98 | A09.1.03.027 |
| TA2 | 3521 |
| FMA | 17742 |
| Anatomical terminology | |
Theendometrium is the innerepithelial layer, along with itsmucous membrane, of themammalianuterus. It has a basal layer and a functional layer: the basal layer containsstem cells which regenerate the functional layer.[1] The functional layer thickens and then is shed duringmenstruation in humans and some other mammals, including otherapes,Old World monkeys, some species ofbat, theelephant shrew[2] and theCairo spiny mouse.[3] In most other mammals, the endometrium is reabsorbed in theestrous cycle. Duringpregnancy, the glands andblood vessels in the endometrium further increase in size and number. Vascular spaces fuse and become interconnected, forming theplacenta, which suppliesoxygen and nutrition to theembryo andfetus.[4][5] The speculated presence of an endometrial microbiota[6]has been argued against.[7][8]
The endometrium consists of a single layer ofcolumnar epithelium plus thestroma on which it rests. The stroma is a layer ofconnective tissue that varies in thickness according tohormonal influences. In theuterus, simpletubular glands reach from the endometrial surface through to the base of the stroma, which also carries a rich blood supply provided by thespiral arteries. In women of reproductive age, two layers of endometrium can be distinguished. These two layers occur only in the endometrium lining the cavity of the uterus, and not in the lining of thefallopian tubes where a potentially life-threateningectopic pregnancy may occur nearby.[4][5]
In the absence of progesterone, the arteries supplying blood to the functional layer constrict, so that cells in that layer becomeischaemic and die, leading tomenstruation.
It is possible to identify the phase of the menstrual cycle by reference to either theovarian cycle or theuterine cycle by observing microscopic differences at each phase—for example in the ovarian cycle:
| Phase | Days | Thickness | Epithelium |
|---|---|---|---|
| Menstrual phase | 1–5 | Thin | Absent |
| Follicular phase | 5–14 | Intermediate | Columnar |
| Luteal phase | 15–27 | Thick | Columnar. Also visible arearcuate vessels of uterus |
| Ischemic phase | 27–28 | Columnar. Also visible are arcuate vessels of uterus |
About 20,000 protein coding genes are expressed in human cells and some 70% of these genes are expressed in the normal endometrium.[9][10] Just over 100 of these genes are more specifically expressed in the endometrium with only a handful genes being highly endometrium specific. The corresponding specific proteins are expressed in the glandular and stromal cells of the endometrial mucosa. The expression of many of these proteins vary depending on the menstrual cycle, for example theprogesterone receptor andthyrotropin-releasing hormone both expressed in the proliferative phase, andPAEP expressed in the secretory phase. Other proteins such as theHOX11 protein that is required for female fertility, is expressed in endometrial stroma cells throughout the menstrual cycle. Certain specific proteins such as theestrogen receptor are also expressed in other types of female tissue types, such as thecervix,fallopian tubes,ovaries andbreast.[11]
The uterus and endometrium was for a long time thought to be sterile. Thecervical plug of mucosa was seen to prevent the entry of anymicroorganisms ascending from the vagina. In the 1980s this view was challenged when it was shown that uterine infections could arise from weaknesses in the barrier of the cervical plug. Organisms from the vaginal microbiota could enter the uterus duringuterine contractions in the menstrual cycle. Further studies sought to identify microbiota specific to the uterus which would be of help in identifying cases of unsuccessfulIVF and miscarriages. Their findings were seen to be unreliable due to the possibility of cross-contamination in the sampling procedures used. The well-documented presence ofLactobacillus species, for example, was easily explained by an increase in the vaginal population being able to seep into the cervical mucous.[7] Another study highlighted the flaws of the earlier studies including cross-contamination. It was also argued that the evidence from studies using germ-free offspring ofaxenic animals (germ-free) clearly showed the sterility of the uterus. The authors concluded that in light of these findings there was no existence of amicrobiome.[8]
The normal dominance of Lactobacilli in the vagina is seen as a marker for vaginal health. However, in the uterus this much lower population is seen as invasive in a closed environment that is highly regulated by female sex hormones, and that could have unwanted consequences. In studies ofendometriosisLactobacillus is not the dominant type and there are higher levels ofStreptococcus andStaphylococcus species. Half of the cases ofbacterial vaginitis showed a polymicrobialbiofilm attached to the endometrium.[7]
The endometrium is the innermost lining layer of theuterus, and functions to prevent adhesions between the opposed walls of themyometrium, thereby maintaining the patency of the uterine cavity.[12] During themenstrual cycle orestrous cycle, the endometrium grows to a thick, blood vessel-rich, glandular tissue layer. This represents an optimal environment for theimplantation of ablastocyst upon its arrival in the uterus. The endometrium is central, echogenic (detectable using ultrasound scanners), and has an average thickness of 6.7 mm.
Duringpregnancy, the glands andblood vessels in the endometrium further increase in size and number. Vascular spaces fuse and become interconnected, forming theplacenta, which suppliesoxygen and nutrition to theembryo andfetus.
The functional layer of the endometrial lining undergoes cyclic regeneration from stem cells in the basal layer.[1] Humans, apes, and some other species display themenstrual cycle, whereas most other mammals are subject to anestrous cycle.[2] In both cases, the endometrium initially proliferates under the influence ofestrogen. However, onceovulation occurs, the ovary (specifically the corpus luteum) will produce much larger amounts ofprogesterone. This changes the proliferative pattern of the endometrium to a secretory lining. Eventually, the secretory lining provides a hospitable environment for one or more blastocysts.
Upon fertilization, the egg may implant into the uterine wall and provide feedback to the body withhuman chorionic gonadotropin (hCG). hCG provides continued feedback throughout pregnancy by maintaining the corpus luteum, which will continue its role of releasing progesterone and estrogen. In case of implantation, the endometrial lining remains asdecidua. The decidua becomes part of the placenta; it provides support and protection for the gestation.
Without implantation of a fertilized egg, the endometrial lining is either reabsorbed (estrous cycle) or shed (menstrual cycle). In the latter case, the process of shedding involves the breaking down of the lining, the tearing of small connective blood vessels, and the loss of the tissue and blood that had constituted it through thevagina. The entire process occurs over a period of several days. Menstruation may be accompanied by a series of uterine contractions; these help expel the menstrual endometrium.
If there is inadequate stimulation of the lining, due to lack of hormones, the endometrium remains thin and inactive. In humans, this will result inamenorrhea, or the absence of a menstrual period. Aftermenopause, the lining is often described as being atrophic. In contrast, endometrium that is chronically exposed to estrogens, but not to progesterone, may becomehyperplastic. Long-term use oforal contraceptives with highly potentprogestins can also induce endometrialatrophy.[13][14]
In humans, the cycle of building and shedding the endometrial lining lasts an average of 28 days. The endometrium develops at different rates in different mammals. Various factors including the seasons, climate, and stress can affect its development. The endometrium itself produces certainhormones at different stages of the cycle and this affects other parts of thereproductive system.
Chorionic tissue can result in marked endometrial changes, known as anArias-Stella reaction, that have an appearance similar tocancer.[15] Historically, this change was diagnosed asendometrial cancer and it is important only in so far as it should not be misdiagnosed as cancer.
Thin endometrium may be defined as an endometrial thickness of less than 8 mm. It usually occurs aftermenopause. Treatments that can improve endometrial thickness includeVitamin E,L-arginine andsildenafil citrate.[17]
Gene expression profiling usingcDNA microarray can be used for the diagnosis of endometrial disorders.[18]TheEuropean Menopause and Andropause Society (EMAS) released Guidelines with detailed information to assess the endometrium.[19]
An endometrial thickness (EMT) of less than 7 mm decreases the pregnancy rate inin vitro fertilization by anodds ratio of approximately 0.4 compared to an EMT of over 7 mm. However, such low thickness rarely occurs, and any routine use of this parameter is regarded as not justified. The optimal endometrial thickness is 10mm. Nevertheless, in human a perfect synchrony is not necessary; if the endometrium is not ready to receive the embryo an ectopic pregnancy may occur. This consist of the implantation of the blast outside the uterus, which can be extremely dangerous.[20]
Observation of the endometrium bytransvaginal ultrasonography is used when administeringfertility medication, such as inin vitro fertilization. At the time ofembryo transfer, it is favorable to have an endometrium of a thickness of between 7 and 14mm with atriple-line configuration,[21] which means that the endometrium contains ahyperechoic (usually displayed as light) line in the middle surrounded by two morehypoechoic (darker) lines. Atriple-line endometrium reflects the separation of the basal layer and the functional layer, and is also observed in the periovulatory period secondary to risingestradiol levels, and disappears after ovulation.[22]
Endometrial thickness is also associated with live births in IVF. The live birth rate in a normal endometrium is halved when the thickness is <5mm.[23]
Estrogens stimulate endometrialproliferation andcarcinogenesis.[24][25][26] Conversely, progestogens inhibit endometrial proliferation and carcinogenesis caused by estrogens and stimulatedifferentiation of the endometrium intodecidua, which is termedendometrial transformation or decidualization.[24][25][26] This is mediated by the progestogenic and functionalantiestrogenic effects of progestogens in this tissue.[25] These effects of progestogens and their protection againstendometrial hyperplasia andendometrial cancer caused by estrogens is referred to asendometrial protection.[24][25][26] As a result of endometrial protection, endometrial cells can undergoepithelial-mesenchymal transition and be detected in menstrual fluid.[27][28]
Endometrial receptivity is a crucial factor in achieving successful embryo implantation in assisted reproduction treatments. It refers to the ability of the endometrium to accept an embryo during a specific time window, known as the "implantation window." The synchronization between endometrial development and the embryo is essential to ensure a successful pregnancy.
Currently, there are three main tests that help evaluate endometrial receptivity and optimize fertility treatments:
ERA (Endometrial Receptivity Analysis):
This genetic test analyzes the expression of specific genes in the endometrium to identify whether it is in a receptive, pre-receptive or post-receptive phase, allowing the ideal moment for embryo transfer to be personalized.
EMMA (Endometrial Microbiome Metagenomic Analysis) andALICE (Analysis of Infectious Chronic Endometritis):
Perform a test on the intrauterine microflora, using a small sample of the endometrium, in order to determine the presence of microorganisms that may promote or harm embryo implantation.
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