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Endometrium

The endometrium is the mucous membrane lining the inner cavity of the uterus, a dynamic tissue composed of simple columnar epithelium overlying a lamina propria rich in glands, stromal cells, and blood vessels, which undergoes cyclic regeneration and shedding in response to ovarian hormones during the menstrual cycle.^[1] It consists of two primary layers: the deeper stratum basalis (basal layer), which remains relatively stable and serves as a regenerative source, and the superficial stratum functionalis (functional layer), which proliferates under estrogen influence, thickens to support potential embryo implantation, and is largely shed during menstruation if no pregnancy occurs.^[2]^[3] The physiological roles of the endometrium center on reproduction, including preparation for blastocyst implantation through vascular and glandular development, maintenance of early pregnancy by providing nutrients and immune modulation, and regulated breakdown leading to menstruation in the absence of fertilization.^[4] Hormonal regulation primarily involves estrogen promoting proliferative growth during the follicular phase and progesterone inducing secretory changes in the luteal phase, with the entire process exhibiting remarkable regenerative capacity post-menstruation.^[2]^[5] This cyclical transformation, occurring approximately every 28 days in reproductive-aged individuals, underscores the endometrium's adaptability, though disruptions can lead to conditions such as hyperplasia or infertility.^[4]

Anatomy and Structure

Gross Anatomy

The endometrium is the innermost mucosal membrane that lines the uterine cavity, serving as the interface for potential embryo implantation. It originates embryonically from the fused paramesonephric (Müllerian) ducts, which give rise to the upper female reproductive tract including the uterus.^[6] This lining covers the entire inner surface of the uterine corpus, extending from the fundus—the dome-shaped superior portion where the fallopian tubes enter at the cornua—to the internal os of the cervix, where it transitions to the endocervical epithelium.^[3] The endometrium is structurally divided into two primary layers visible on gross examination or imaging. The basal layer (stratum basalis) forms the deeper, permanent portion adjacent to the underlying myometrium, remaining relatively unchanged across the menstrual cycle and providing the regenerative base for the overlying tissue. The functional layer (stratum functionalis), comprising the superficial two-thirds of the endometrium, undergoes dynamic proliferation and is cyclically shed during menstruation as menstrual effluent.^[2] This division is evident in cross-sections of the uterus, with the functional layer appearing more prominent during the luteal phase. Endometrial thickness exhibits significant variation throughout the menstrual cycle in non-pregnant individuals, reflecting its responsiveness to hormonal cues. It measures approximately 2-4 mm during the menstrual phase, increases to 5-7 mm in the early proliferative phase, reaches up to 11 mm in the late proliferative phase, and attains 12-16 mm (or up to 18 mm) in the secretory phase.^[7] ^[8] Regionally, the endometrium is thicker in the fundus and upper body compared to the isthmus and lower uterine segment, optimizing conditions for implantation near the tubal ostia. The vascular architecture of the endometrium supports its metabolic demands and cyclic remodeling. Nutrient delivery occurs primarily via branches of the uterine arteries, which form arcuate arteries within the outer myometrium; these give rise to radial arteries that penetrate inward. Within the endometrium, the radial arteries branch into straight basal arteries supplying the stable basal layer and coiled spiral arteries perfusing the functional layer, ensuring oxygenation and nutrient supply critical for proliferation and potential pregnancy support.^[3] The spiral arteries, in particular, elongate and become more tortuous during the secretory phase to accommodate increased blood flow.^[9]

Histology

The endometrium is lined by a simple columnar surface epithelium consisting of ciliated and non-ciliated secretory cells that facilitate transport and nutrient provision within the uterine cavity.^[10] These epithelial cells form a continuous layer over the luminal surface, with cilia providing motility and secretory cells producing glycoproteins and other substances essential for reproductive functions.^[11] Embedded within the endometrium are tubular endometrial glands lined by similar simple columnar epithelium, which exhibit phase-specific morphology: straight and narrow during the proliferative phase, becoming tortuous and coiled in the secretory phase to support implantation.^[10] These glands extend from the surface epithelium deep into the stromal layer, varying in density and branching pattern across the tissue.^[12] The stromal compartment forms a compact, cellular matrix primarily composed of fibroblasts embedded in an extracellular matrix rich in collagens, proteoglycans, and laminins, which provides structural support and undergoes dynamic remodeling.^[13] Interspersed among the fibroblasts are leukocytes, contributing to immune surveillance and tissue homeostasis.^[14] Histologically, the endometrium is stratified into two distinct layers: the basal layer, adjacent to the myometrium, which contains relatively inactive, coiled glands and dense stroma that remains intact post-menstruation; and the functional layer, the superficial zone that includes responsive glands and edematous stroma, which proliferates and is shed cyclically.^[10] The basal layer serves as a regenerative reservoir, while the functional layer exhibits marked changes during the menstrual cycle.^[3] Immune cells are integral to endometrial histology, with uterine natural killer (uNK) cells comprising up to 70% of leukocytes in the stroma during the secretory phase, alongside macrophages that modulate inflammation and tissue repair.^[15] These cells are predominantly located in the stromal interstices, influencing vascular remodeling and immune tolerance.^[16]

Molecular and Cellular Composition

The endometrium exhibits significant cellular heterogeneity, primarily comprising epithelial and stromal cells with distinct molecular markers that define their identities and functions. Epithelial cells, which line the endometrial glands and surface, express cytokeratin 7 (CK7), a intermediate filament protein that maintains structural integrity and polarity in these cells.^[17] In contrast, stromal cells, forming the supportive connective tissue matrix, are characterized by vimentin expression, an intermediate filament essential for their mesenchymal properties, and CD10, a cell surface metalloprotease that aids in extracellular matrix remodeling.^[18] These markers highlight the compartmentalized organization of the endometrium, where epithelial cells provide a protective barrier and stromal cells facilitate dynamic tissue responses. Key proteins underpin the endometrium's molecular architecture, particularly in adhesion, signaling, and hormonal responsiveness. Integrins, such as αvβ3, serve as cell adhesion molecules on the endometrial surface, binding extracellular matrix components like osteopontin to mediate embryo attachment during implantation.^[19] Cytokines including leukemia inhibitory factor (LIF) promote endometrial receptivity by enhancing immune tolerance and trophoblast differentiation at the maternal-fetal interface.^[20] Progesterone receptors (PR-A and PR-B isoforms) are nuclear receptors that transduce progesterone signals, regulating gene transcription to support secretory differentiation and suppress estrogen-driven proliferation in the endometrium. These proteins collectively ensure the tissue's preparedness for reproductive events. Gene expression profiles in the endometrium vary cyclically, reflecting phase-specific molecular adaptations. In the secretory phase, homeobox gene HOXA10 is upregulated in stromal cells, driving decidualization and receptivity through transcriptional control of downstream targets involved in implantation.^[21] Mucins, such as MUC1 and MUC16, function in the epithelial layer to form a glycocalyx barrier that protects against microbial invasion and modulates cell signaling, with their expression peaking in the proliferative phase to maintain luminal integrity.^[22] Growth factors like vascular endothelial growth factor (VEGF) are induced in both epithelial and stromal compartments during the secretory phase, promoting angiogenesis to vascularize the thickening endometrium for nutrient support.^[23] The endometrial microbiome contributes to the tissue's molecular milieu, with a healthy composition dominated by Lactobacillus species that produce lactic acid to maintain an acidic environment and inhibit pathogen overgrowth.^[24] Dysbiosis, characterized by reduced Lactobacillus abundance and increased diversity of anaerobes like Gardnerella, is associated with elevated inflammatory cytokines such as IL-6 and IL-8, potentially disrupting epithelial barrier function and receptivity.^[25] Recent analyses indicate that this microbial imbalance may influence local immune responses, though direct causal links to endometrial health require further elucidation from 2024 prospective studies.

Development and Regeneration

Embryonic and Postnatal Development

The endometrium originates from the paramesonephric (Müllerian) ducts, which emerge as paired invaginations of the coelomic epithelium along the urogenital ridge during the sixth week of gestation. These ducts elongate caudally, guided by interactions with the mesonephric (Wolffian) ducts, and reach the urogenital sinus by the eighth week, setting the foundation for the upper female reproductive tract. Genetic factors, including WNT signaling pathways—particularly WNT9B secreted from the mesonephric ducts—play a critical role in promoting duct elongation and differentiation into uterine precursors.^[26]^[27] Between the ninth and tenth weeks of gestation, the caudal portions of the paramesonephric ducts fuse in the midline to form the uterovaginal primordium, a key step in establishing the uterine body. This fusion is followed by canalization, where a central lumen develops through vacuolization and apoptosis-mediated remodeling, creating the uterine cavity by approximately week 12. Concurrently, the endometrium differentiates as the innermost mucosal layer lining this cavity, with initial stromal and epithelial components arising from the ductal mesenchyme and epithelium (both of mesodermal origin). Vascularization patterns emerge during this period, as branches from the uterine arteries penetrate the stroma to form a primitive capillary network supporting tissue expansion.^[28]^[29] Primitive endometrial glands begin to appear as solid epithelial buds invaginating from the luminal surface around 16-20 weeks gestation, marking a major milestone in endometrial histogenesis; these buds canalize in the second trimester to form tubular structures.^[30]^[31] Recent single-cell transcriptomic analyses have highlighted the role of WNT signaling in specifying ductal epithelial progenitors during this phase, with spatiotemporal expression patterns guiding differentiation into endometrial lineages.^[30] Postnatally, the endometrium remains quiescent until puberty, around ages 10-14, when rising ovarian estrogen production drives proliferative growth and maturation. While initiated prenatally, full glandular proliferation and maturation occur postnatally under hormonal influence. This estrogen-mediated process induces endometrial thickening, glandular proliferation, and the establishment of the distinct functional (superficial) and basal (deep) layers, preparing the tissue for cyclic regeneration. Initial layering reflects the differential response of stromal and epithelial cells to hormonal cues, with the basal layer serving as a reservoir for renewal.^[28]

Stem Cells and Tissue Regeneration

The endometrium harbors distinct populations of stem and progenitor cells that drive its remarkable regenerative capacity. Endometrial stem/progenitor cells, primarily located in the basal layer, include epithelial progenitors and mesenchymal stromal/stem cells (eSCs), which exhibit self-renewal and multipotency. These cells are responsible for replenishing the tissue following menstrual shedding. Additionally, side population (SP) cells, comprising approximately 2% of endometrial cells, display stem-like properties such as efflux of Hoechst 33342 dye via ABC transporters and contribute to both stromal and epithelial compartments, though they are predominantly perivascular in origin.^[32]^[33] The regenerative cycle of the endometrium involves the monthly shedding of the functional layer, which constitutes the upper two-thirds of the tissue thickness, while the basal layer remains intact and serves as a reservoir for repopulation. Stem/progenitor cells from the basalis migrate upward to reconstruct the functionalis within days post-menstruation, ensuring rapid repair without scarring. This process is supported by mechanisms identified through clonogenic assays, which demonstrate the presence of highly proliferative epithelial and stromal cells capable of forming colonies in vitro, and label-retaining cell (LRC) studies using bromodeoxyuridine (BrdU), which highlight slow-cycling quiescent cells in the basal glands and stroma that act as long-term progenitors. Molecular markers such as SUSD2 for stromal progenitors and N-cadherin for epithelial ones further characterize these populations.^[34]^[35]^[36] Stem cell niches in the endometrium are predominantly perivascular, where eSCs reside in close association with blood vessels, receiving cues from endothelial cells and pericytes to maintain quiescence or activate proliferation. The extracellular matrix (ECM) plays a critical role in these niches by providing structural support and signaling via integrins and growth factors, dynamically remodeling during regeneration to guide progenitor migration and differentiation. Recent advances include organoid models derived from endometrial stem cells, which recapitulate glandular architecture and hormonal responses to study regeneration in vitro, enabling high-throughput testing of repair mechanisms. Therapeutically, bone marrow-derived mesenchymal stem cells (BM-MSCs) have shown promise in treating thin endometrium, a condition impairing fertility, by promoting vascularization and tissue thickening in preclinical and early clinical trials as of 2024-2025, with autologous approaches enhancing engraftment and reducing fibrosis.^[37]

Physiology

Hormonal Regulation

The endometrium is primarily regulated by the hypothalamic-pituitary-ovarian (HPO) axis, which orchestrates the cyclic production of steroid hormones that drive its structural and functional changes. The hypothalamus releases gonadotropin-releasing hormone (GnRH) in pulsatile fashion, stimulating the anterior pituitary to secrete follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which in turn induce ovarian follicle development and estrogen/progesterone synthesis. These ovarian hormones act on endometrial receptors to coordinate proliferation, differentiation, and maintenance, with disruptions in the HPO axis leading to altered endometrial responsiveness.^[38] Estrogen, primarily estradiol from growing ovarian follicles, promotes endometrial proliferation through estrogen receptor alpha (ERα), which is highly expressed in stromal and epithelial cells. ERα activation induces the expression of growth factors such as insulin-like growth factor-1 (IGF-1) and epidermal growth factor (EGF), which mediate epithelial hyperplasia and stromal expansion via paracrine signaling. This proliferative response is essential for thickening the endometrial lining to support potential implantation.^[39]^[40]^[41] Progesterone, secreted by the corpus luteum post-ovulation, induces secretory differentiation of the endometrium via progesterone receptors (PR), particularly PR-B isoform, which predominates in glandular epithelium. PR signaling upregulates genes involved in nutrient secretion and glandular maturation while suppressing estrogen-driven mitosis through inhibition of ERα activity and cell cycle progression. This antagonistic balance prevents uncontrolled growth and prepares the endometrium for embryo attachment.^[42]^[43]^[44] Other hormones contribute to specialized endometrial adaptations; relaxin, produced by the corpus luteum, facilitates vascular remodeling by promoting angiogenesis and increasing endothelial cell permeability in endometrial arterioles, enhancing blood flow and tissue preparedness. Human chorionic gonadotropin (hCG), secreted by the early embryo and placenta, sustains endometrial integrity during pregnancy by maintaining progesterone production from the corpus luteum and directly modulating stromal decidualization to support trophoblast invasion.^[45]^[46]^[47] Recent single-cell transcriptomic atlases have elucidated hormone-responsive cell clusters in the endometrium, revealing distinct stromal subpopulations that dynamically express ERα and PR in response to cyclic steroid fluctuations. For instance, the Human Endometrial Cell Atlas (HECA), integrating over 300,000 cells across menstrual phases, identifies perivascular and inflammatory stromal clusters as key mediators of estrogen-induced proliferation and progesterone-mediated immune modulation. These insights highlight heterogeneous cellular responses that underpin endometrial plasticity.^[48]

Menstrual Cycle Phases

The menstrual cycle typically lasts 28 days on average, though individual variations range from 21 to 35 days, which can affect the synchrony between endometrial development and ovulation timing.^[49] These variations influence the precise alignment of endometrial maturation with the ovulatory window, potentially impacting fertility.^[50] During the menstrual phase, spanning days 1 to 5, the functional layer of the endometrium undergoes shedding due to the withdrawal of progesterone following corpus luteum regression. This process involves localized ischemia and enzymatic degradation of the extracellular matrix, leading to the sloughing of the upper two-thirds of the endometrium.^[51] Hemostasis is achieved through constriction of spiral arteries, which reduces blood flow and promotes clot formation to limit bleeding.^[49] The basal layer remains intact, providing the foundation for subsequent regeneration. The proliferative phase, from days 6 to 14, is characterized by estrogen-driven regrowth of the endometrium from the basal layer remnants. Glandular epithelia proliferate and straighten, while the stroma exhibits mitotic activity and edema, resulting in an increase in endometrial thickness from about 2 mm to 10-12 mm by the end of this phase.^[50] Pseudostratification of glandular cells and prominent stromal mitoses serve as key histological markers of this estrogen-dominated period.^[49] In the secretory phase, encompassing days 15 to 28, progesterone induces further transformations in the endometrium to prepare for potential implantation. Glands become coiled and dilated, with the appearance of subnuclear vacuoles in epithelial cells around days 17-18, followed by accumulation of glycogen and secretory material.^[50] Stromal changes include edema and the development of predecidual reactions, where fibroblasts enlarge and accumulate glycogen near spiral arterioles.^[51] Histological hallmarks include the absence of mitoses, presence of glycogen-rich secretions, and progressive glandular tortuosity, distinguishing this phase from the proliferative period.^[49] These progesterone-mediated adaptations peak in the late secretory phase, setting the stage for either menstruation or pregnancy maintenance if implantation occurs.

Reproductive Functions

Endometrial Receptivity

The endometrial receptivity, or window of implantation (WOI), represents a brief period during which the uterus is optimally prepared for embryo attachment, typically occurring between days 20 and 24 of a 28-day menstrual cycle or 6 to 10 days after the luteinizing hormone (LH) surge.^[52] This temporal restriction ensures synchronized embryo-uterine interactions, lasting approximately 48 hours in humans.^[53] Disruptions in this window can lead to implantation failure, highlighting its critical role in reproductive success. Molecular markers are essential indicators of endometrial receptivity, with integrin αvβ3 expression emerging in the glandular and luminal epithelium during the mid-secretory phase as a key adhesion molecule for trophoblast attachment.^[54] HOXA10, a homeobox transcription factor, is upregulated in the stromal compartment under progesterone influence, regulating downstream genes including integrins to facilitate receptivity.^[55] These markers reflect the transition from a non-receptive to a receptive state, with their coordinated expression confirming uterine preparedness. Several factors influence the acquisition and maintenance of endometrial receptivity, primarily through progesterone priming that induces stromal differentiation and epithelial remodeling.^[56] Cytokine balance is crucial, with interleukin-11 (IL-11) promoting stromal decidualization and heparin-binding epidermal growth factor-like growth factor (HB-EGF) enhancing epithelial-trophoblast signaling via EGFR activation.^[57] Estrogen modulates these processes in concert with progesterone, ensuring a receptive milieu without excessive inflammation. Assessment of endometrial receptivity often employs the endometrial receptivity array (ERA), a transcriptomic tool analyzing over 200 genes from a timed biopsy to identify the personalized WOI, typically shifting transfer timing by 12 to 36 hours in about 25% of cases.^[58] This method enables tailored frozen embryo transfers, improving outcomes in patients with recurrent implantation failure by aligning progesterone exposure with individual gene expression profiles.^[59] Recent single-cell RNA sequencing studies have elucidated epithelial-stromal crosstalk during receptivity, revealing dynamic ligand-receptor interactions such as CXCL12-CXCR4 signaling that coordinates stromal support for epithelial adhesion molecules.^[60] These analyses, including time-series profiling of luteal-phase endometria, demonstrate heterogeneous stromal subpopulations responding to progesterone, with implications for understanding receptivity variations across species and conditions.^[61]

Implantation and Decidualization

Implantation of the blastocyst in the human endometrium is a critical early event in pregnancy, occurring approximately 6-10 days after fertilization during the mid-secretory phase of the menstrual cycle. The process unfolds in sequential stages: apposition, where the blastocyst loosely contacts the endometrial surface; adhesion, involving stable attachment mediated by integrins and other adhesion molecules; and invasion, during which trophoblast cells from the blastocyst penetrate the endometrial epithelium and stroma to establish a connection with the maternal circulation.^[62] This invasion is facilitated by the secretion of proteases from trophoblast cells, which degrade the extracellular matrix, allowing deeper embedding of the embryo.^[63] Successful implantation requires precise synchronization with the endometrial receptivity window, though the active interaction here emphasizes trophoblast-driven progression.^[64] Concurrent with implantation, the endometrium undergoes decidualization, a progesterone-driven differentiation of stromal fibroblasts into decidual cells, which provides structural support and immunological protection for the developing embryo. These decidual cells exhibit morphological changes, including cytoplasmic enlargement and accumulation of glycogen and lipids, while secreting key factors such as prolactin and insulin-like growth factor binding protein-1 (IGFBP-1) to regulate local growth and immune responses.^[65] Prolactin production, in particular, peaks in decidual tissue and contributes to maternal immune modulation, whereas IGFBP-1 inhibits IGF actions to prevent excessive trophoblast proliferation.^[66] This transformation begins in the late secretory phase and intensifies post-implantation, ensuring a hospitable environment for placentation.^[67] Vascular remodeling accompanies these events, primarily involving the modification of endometrial spiral arteries by invading extravillous trophoblasts to form low-resistance conduits for placental blood flow. This process entails the loss of endothelial and smooth muscle layers in the arteries, replaced by fibrinoid deposits and trophoblast cells, which widens the vessel lumens and enhances perfusion to the intervillous space.^[68] Incomplete remodeling can impair nutrient delivery, but in normal physiology, it supports fetal development from the first trimester onward.^[69] Notably, 10–40% of conceptions fail at the implantation stage due to desynchronization or inadequate trophoblast invasion, contributing significantly to early pregnancy loss.^[70] Recent advances in modeling implantation leverage 3D organoids derived from endometrial stem cells, integrated with microfluidic systems to simulate dynamic embryo-endometrium interactions. These vascularized endometrial complexes recapitulate apposition, adhesion, and invasion, allowing study of paracrine signaling and mitochondrial function in a controlled environment.^[71] Such 2025 innovations, including triple-cellular assembloids, provide platforms for testing therapeutic interventions without relying on animal models, enhancing understanding of implantation fidelity.^[72]

Pathology

Benign Disorders

Benign disorders of the endometrium encompass a range of non-cancerous conditions that can disrupt normal uterine function, often presenting with abnormal uterine bleeding or fertility challenges. These abnormalities arise from hormonal imbalances, trauma, or infectious processes, leading to structural or inflammatory changes within the endometrial lining. Common examples include endometrial hyperplasia, polyps, thin endometrium, Asherman's syndrome, and endometritis, each with distinct pathophysiology and clinical implications. Endometrial hyperplasia represents an abnormal proliferation of the endometrial glands and stroma, typically driven by unopposed estrogen exposure from conditions such as anovulation, obesity, or exogenous estrogen therapy. It is classified into simple hyperplasia, characterized by increased gland number without significant architectural complexity, and atypical hyperplasia, which features cytologic atypia and glandular crowding, indicating a higher premalignant potential. Simple hyperplasia carries a low risk of progression to endometrial carcinoma, estimated at 1-3% over 10-20 years, whereas atypical hyperplasia has a substantially elevated risk, ranging from 8% annually if untreated to approximately 23% overall progression rate.^[73]^[74] Endometrial polyps are focal, benign overgrowths of endometrial tissue, often pedunculated or sessile, containing glands, stroma, and blood vessels, and frequently associated with tamoxifen use or hormonal influences. They commonly manifest as abnormal uterine bleeding, including intermenstrual spotting or heavy menstrual flow, and can contribute to infertility in up to 35% of affected cases by interfering with implantation. Prevalence among reproductive-aged women varies from 7.8% to 24%, with higher detection rates in those undergoing evaluation for bleeding, where polyps account for about 25% of findings.^[75]^[76] Thin endometrium, defined as an endometrial thickness of less than 7 mm in the mid-luteal phase on ultrasound, impairs receptivity to embryo implantation and is linked to reduced fertility outcomes, with pregnancy rates dropping significantly below this threshold. Common causes include endometrial scarring from prior surgeries, infections, or radiation, which disrupt the regenerative capacity of the basal layer, sometimes referencing defects in stem cell-mediated tissue renewal. This condition is particularly problematic in assisted reproduction, where thicknesses under 7 mm correlate with implantation failure rates exceeding 50% in some cohorts.^[77]^[78] Asherman's syndrome involves the formation of intrauterine adhesions or synechiae, resulting in partial or complete obliteration of the uterine cavity, most often following traumatic procedures like dilation and curettage after pregnancy loss or abortion. These fibrotic bands arise from basal endometrial layer injury, leading to amenorrhea, hypomenorrhea, or recurrent miscarriages due to reduced cavity volume and impaired vascularization. Diagnosis is best confirmed via hysteroscopy, which allows direct visualization and classification of adhesion extent, with ultrasound or hysterosalpingography serving as initial screening tools.^[79]^[80] Endometritis refers to inflammation of the endometrium, typically acute or chronic, caused by ascending infection from the lower genital tract, with bacterial profiles deviating markedly from the normal low-biomass endometrial microbiome dominated by Lactobacillus species. Acute endometritis often involves pathogens such as group B Streptococcus, Escherichia coli, or Enterococcus, presenting with postpartum fever and purulent discharge, while chronic forms feature plasma cell infiltration and altered microbiota including higher abundances of Faecalibacterium or Escherichia-Shigella compared to healthy norms. These infections can lead to scarring and fertility compromise if untreated, highlighting the importance of distinguishing pathogenic overgrowth from commensal flora.^[81]^[82]^[83]

Endometrial Cancer

Endometrial cancer encompasses malignant neoplasms arising from the glandular epithelium of the endometrium, representing a significant portion of gynecologic malignancies. Globally, its incidence is rising, with an estimated 420,368 new cases diagnosed in 2022, driven by factors such as increasing obesity rates and aging populations.^[84] It accounts for approximately 28% of gynecologic cancers globally, though this proportion varies by region, with higher rates in high-income countries.^[85] The disease primarily affects postmenopausal women, but cases in premenopausal individuals occur, often linked to unopposed estrogen exposure. Early detection through abnormal uterine bleeding evaluation contributes to a generally favorable prognosis for localized disease, with five-year survival exceeding 80% for stage I cases.^[86] Endometrial cancers are broadly classified into type I and type II based on histopathological features, clinical behavior, and molecular underpinnings. Type I tumors, which constitute about 80-90% of cases, are typically low-grade endometrioid adenocarcinomas driven by estrogen excess and frequently preceded by endometrial hyperplasia.^[87] These estrogen-related neoplasms exhibit microsatellite instability or PTEN mutations and generally have a better prognosis due to their indolent growth. In contrast, type II tumors, comprising 10-20% of cases, include high-grade serous and clear cell carcinomas that are estrogen-independent, aggressive, and often associated with TP53 mutations leading to genomic instability.^[88] These non-endometrioid subtypes arise de novo without a hyperplastic precursor and carry a poorer prognosis, with higher rates of extrauterine spread at diagnosis.^[89] Key risk factors for endometrial cancer include obesity, which elevates circulating estrogen levels through aromatization in adipose tissue and accounts for roughly one-third of cases in high-income settings.^[90] Tamoxifen therapy for breast cancer increases risk modestly, with an annual incidence of less than 1% among users, primarily for endometrioid subtypes.^[91] Hereditary predisposition, notably Lynch syndrome due to germline mismatch repair (MMR) gene defects, confers a cumulative risk of 15-30% by age 70, with MMR deficiency promoting microsatellite instability in tumors.^[92] Staging follows the International Federation of Gynecology and Obstetrics (FIGO) system, which categorizes disease from stage I (tumor confined to the uterine corpus) to stage IV (distant metastasis, including involvement of bladder, bowel, or extra-abdominal sites).^[93] The 2023 FIGO revision refines substages by integrating histopathological patterns, lymphovascular invasion, and molecular data, enhancing prognostic accuracy—for instance, upstaging certain aggressive histotypes even if confined to the uterus.^[94] Molecular classification, pioneered by The Cancer Genome Atlas (TCGA) in 2013, delineates four prognostically distinct subtypes through integrated genomic profiling of 373 tumors: POLE ultramutated (characterized by proofreading domain mutations in POLE, yielding the best outcomes with >95% five-year survival); microsatellite instability hypermutated (MSI, often MMR-deficient, with intermediate prognosis); copy-number low (CNL, endometrioid-like, favorable to intermediate); and copy-number high (CNH, serous-like with TP53 abnormalities, poorest prognosis).^[95] This framework has been validated across cohorts and informs adjuvant therapy decisions, such as de-escalation for POLE subtypes. Updates as of 2025, including the PORTEC-4a trial results presented at ESTRO 2025 showing that molecular profiling can safely reduce the need for radiotherapy in women with early-stage endometrial cancer (e.g., omitting RT in low-risk p53 wild-type/no specific molecular profile stage I disease), and consensus guidelines, emphasize routine testing for these subtypes to refine risk stratification, with POLE and MSI tumors showing improved survival independent of stage, while CNH predicts recurrence risk.^[96]^[97]

Endometriosis

Endometriosis is defined as the presence of endometrial-like glands and stroma outside the uterine cavity, where this ectopic tissue responds to hormonal stimulation similarly to the normal endometrium but in abnormal locations. It affects approximately 10% of women of reproductive age worldwide, equating to about 190 million individuals. Common sites include the ovaries, where it often forms endometriomas or "chocolate cysts," the pelvic peritoneum, fallopian tubes, and uterosacral ligaments. The condition is classified into four stages by the American Society for Reproductive Medicine (ASRM): stage I (minimal, superficial lesions), stage II (mild, more widespread superficial lesions), stage III (moderate, with deep lesions and small cysts on one or both ovaries), and stage IV (severe, with large cysts, dense adhesions, and extensive deep lesions). Diagnosis is often delayed, with an average interval of 7 years from symptom onset to confirmation, due to nonspecific symptoms and challenges in noninvasive detection. The pathogenesis of endometriosis involves multiple theories, with retrograde menstruation—first proposed by Sampson in 1927—being the most widely accepted, positing that viable endometrial fragments reflux through the fallopian tubes into the peritoneal cavity during menstruation. This is supported by the role of endometrial stem or progenitor cells, which may migrate via this route or through lymphatic and vascular dissemination, enabling implantation and survival in ectopic sites. Immune dysregulation further contributes, as impaired peritoneal immune surveillance fails to clear these fragments, allowing chronic inflammation, angiogenesis, and fibrosis; for instance, reduced natural killer cell activity and altered cytokine profiles in the peritoneal fluid promote lesion persistence. Symptoms primarily include dysmenorrhea (painful periods), chronic pelvic pain, and dyspareunia (painful intercourse), which can significantly impair quality of life. Infertility affects 30-50% of women with endometriosis, potentially due to distorted pelvic anatomy, inflammation-induced ovulatory dysfunction, or impaired oocyte quality, though the exact mechanisms remain under investigation. Unlike the eutopic endometrium within the uterus, ectopic endometrial tissue exhibits distinct molecular profiles, such as elevated aromatase (CYP19A1) expression leading to local estrogen production that fuels lesion growth—up to 500-fold higher than in normal endometrium. Ectopic lesions also show altered gene expression in pathways related to inflammation, cell adhesion, and steroid metabolism, differing from eutopic tissue; a 2025 review highlighted how studies often mislabel or over-interpret eutopic samples as representative of ectopic lesions, underscoring these unequivocal differences.^[98]

Clinical Aspects

Diagnosis and Imaging

Diagnosis of endometrial conditions often begins with biopsy techniques to obtain tissue samples for histopathological analysis. The Pipelle endometrial sampling method, an office-based procedure involving a thin, flexible catheter inserted through the cervix to aspirate endometrial tissue, is widely used for detecting hyperplasia and cancer in women presenting with abnormal uterine bleeding.^[99] This technique samples approximately 4% of the endometrial surface and achieves a sensitivity of up to 97% for endometrial carcinoma, making it a first-line diagnostic tool due to its simplicity, low cost, and minimal discomfort.^[100] For more targeted sampling, hysteroscopy-directed biopsy allows direct visualization of the endometrial cavity using a hysteroscope, enabling precise collection of tissue from suspicious areas, which improves diagnostic accuracy for hyperplasia and malignancy compared to blind methods.^[101] Hysteroscopy-guided biopsies demonstrate higher sensitivity in identifying uterine lesions, including endometrial cancer, with studies showing superior performance over dilatation and curettage.^[102] Imaging modalities play a crucial role in non-invasive evaluation of the endometrium. Transvaginal ultrasound (TVUS) is the initial imaging method for assessing endometrial thickness, where a thickness greater than 4-5 mm in postmenopausal women with bleeding prompts further investigation for pathology such as hyperplasia or cancer.^[103] TVUS provides accurate measurement of the endometrial echo in the anterior-posterior dimension, serving as a triage tool with high negative predictive value when thickness is less than 3-4 mm.^[104] For enhanced intracavitary assessment, saline infusion sonohysterography (SIS) involves instilling sterile saline into the uterus during TVUS to distend the cavity, improving detection of focal lesions like polyps, which appear as hyperechoic structures filling defects.^[105] SIS offers sensitivity and specificity of around 87% and 86%, respectively, for diagnosing endometrial polyps, outperforming standard TVUS in identifying submucosal abnormalities.^[106] Advanced imaging and endoscopic techniques are employed for staging and specific disorders. Magnetic resonance imaging (MRI) is recommended for preoperative staging of endometrial cancer, providing detailed assessment of myometrial invasion, cervical involvement, and lymph node status with an accuracy of approximately 74-85%.^[107] MRI protocols tailored for endometrial cancer include T2-weighted and diffusion-weighted sequences to evaluate tumor depth and extent, aiding in risk stratification per FIGO guidelines.^[108] Hysteroscopy is particularly valuable for diagnosing intrauterine adhesions in Asherman's syndrome, where it visualizes synechiae as fibrous bands obstructing the cavity, allowing for concurrent therapeutic intervention if needed.^[79] This direct endoscopic approach confirms the presence, extent, and severity of adhesions with high precision, guiding management in cases of infertility or amenorrhea.^[109] Biomarkers complement imaging and biopsy in endometrial evaluation. Serum CA-125 levels are elevated in endometriosis, particularly advanced stages, but exhibit limited specificity due to increases in other conditions like ovarian cancer or benign gynecologic disorders, restricting its use as a standalone diagnostic marker.^[110] In endometrial cancer, genomic profiling through next-generation sequencing identifies molecular subtypes, such as POLE-mutated or microsatellite instability-high tumors, informing prognosis and targeted therapies with high clinical utility.^[111] Comprehensive genomic assays on biopsy samples detect actionable alterations in up to 30-40% of cases, enhancing personalized diagnostic and staging approaches.^[112] Recent advancements include AI-enhanced ultrasound for assessing endometrial receptivity, integrating radiomic features from TVUS images with machine learning models like XGBoost to predict implantation potential non-invasively, particularly in recurrent pregnancy loss contexts.^[113] These AI tools, evaluated in 2024 studies, achieve high accuracy in evaluating endometrial volume and texture, supporting receptivity assessment alongside emerging stem cell research on regenerative therapies.^[114]

Treatment and Protective Measures

Treatment of endometrial disorders primarily involves targeted hormonal therapies and surgical interventions tailored to the specific pathology. For endometrial hyperplasia, progestins such as medroxyprogesterone acetate or levonorgestrel are recommended as first-line conservative management, particularly in patients desiring fertility preservation, with regression rates exceeding 80% in non-atypical cases after 3-6 months of therapy.^[115]^[116] In endometrial cancer, total hysterectomy with bilateral salpingo-oophorectomy remains the standard surgical approach for early-stage disease, achieving cure rates over 90% in stage I cases.^[117] For endometriosis, gonadotropin-releasing hormone (GnRH) agonists like leuprolide are effective in alleviating pelvic pain and reducing lesion size, with symptom relief in up to 70% of patients after 6 months of treatment, though hypoestrogenic side effects necessitate add-back therapy.^[118] Regenerative therapies have emerged as promising options for refractory thin endometrium in assisted reproductive technology (ART) contexts. Stem cell infusions, particularly mesenchymal stem cells derived from bone marrow or umbilical cord, have demonstrated improvements in endometrial thickness by 2-4 mm and enhanced pregnancy rates in clinical trials conducted through 2025, promoting angiogenesis and tissue repair via paracrine mechanisms.^[119]^[120] Similarly, platelet-rich plasma (PRP) intrauterine infusions, an advancing biotech approach in 2025, increase endometrial receptivity by boosting vascularization and reducing fibrosis, yielding clinical pregnancy rates of 40-50% in women with prior implantation failures.^[121]^[122] Protective measures focus on modifiable risk factors to maintain endometrial health. Combined oral contraceptives (COCs) reduce the incidence of endometrial hyperplasia by 50-80% through continuous progestin exposure that opposes estrogen stimulation, offering long-term prevention in high-risk women.^[123] Lifestyle interventions, including sustained weight management via diet and exercise, lower endometrial cancer risk by up to 59% in obese individuals, as evidenced by meta-analyses of bariatric surgery outcomes that mitigate hyperinsulinemia and chronic inflammation.^[124] In ART settings, optimizing embryo transfer protocols enhances endometrial receptivity. Frozen embryo transfer (FET) cycles outperform fresh transfers in achieving higher live birth rates (up to 10-15% improvement) by allowing natural hormonal recovery and better synchronization of the endometrial window.^[125] The levonorgestrel-releasing intrauterine system (LNG-IUS) supports fertility preservation in hyperplasia management, with complete response rates of 70-90% and subsequent conception rates around 50% in treated patients.^[126] Procedures like hysteroscopy for endometrial evaluation or intervention carry low complication rates, including uterine perforation in approximately 1% of cases, underscoring their safety profile.^[127]

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Meta-analysis of mesenchymal stem cell therapy for intrauterine ...
Aug 13, 2025 · Specific results showed that stem cell therapy had significant advantages in improving menstruation, improving pregnancy outcome, increasing ...
[121]
Evaluating the Effectiveness of Platelet Rich Plasma Therapy in ...
Apr 21, 2025 · Numerous studies have reported that intrauterine PRP treatment leads to increased endometrial thickness and better clinical pregnancy outcomes.
[122]
Platelet-rich plasma therapy enhances endometrial receptivity in thin ...
PRP therapy significantly enhances endometrial receptivity and improves pregnancy outcomes in patients with refractory thin endometrium. It offers a promising ...
[123]
Endometrial Hyperplasia Risk in Relation to Recent Use of Oral ...
The present study found a strong reduction in risk of EH among recent users of oral contraceptives (OR=0.2, 95% CI: 0.0–0.6). Previous case-control studies, ...
[124]
Intentional weight loss, weight cycling, and endometrial cancer risk
The meta-analysis yielded a 59% lower risk of endometrial cancer following bariatric surgery (OR 0.41, 95% CI 0.22 to 0.74). Conclusions. Our findings support ...Original Article · Study Characteristics · Synthesis Of Results
[125]
The comparison of pregnancy outcomes in fresh and frozen embryo ...
A significant rate of ongoing and clinical pregnancy has been reported in FET compared to fresh embryos (5). Another study showed no significant difference in ...
[126]
Efficacy of fertility-sparing treatment with LNG-IUS is ... - PubMed
Efficacy of fertility-sparing treatment with LNG-IUS is associated with different ProMisE subtypes of endometrial carcinoma or atypical endometrial hyperplasia.
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Hysteroscopy Treatment & Management - Medscape Reference
Jun 16, 2025 · Perforation and cervical trauma are 2 of the most common complications of hysteroscopy, with uterine perforation rates of approximately 0.7-0.8% ...Preoperative Details · Intraoperative Details · Postoperative Details · Complications