Is Adenomyosis Genetic? A Closer Look at Tissue Changes

Adenomyosis occurs when endometrial-like tissue grows into the muscular wall of the uterus, causing heavy periods and pelvic pain. While the exact cause remains unclear, researchers are investigating genetic factors that may contribute to its development. Identifying genetic influences could improve diagnosis and treatment. Scientists are examining how inherited traits, molecular mechanisms, and environmental factors interact in uterine tissue changes.

Genetic Links in Uterine Tissue Changes

Recent research suggests genetic factors influence adenomyosis by altering uterine tissue structure and function. Genome-wide association studies (GWAS) have identified genetic variants more common in individuals with the condition. A study in Nature Genetics found polymorphisms in MMP2 and MMP9—genes involved in extracellular matrix remodeling—were linked to a higher likelihood of abnormal endometrial infiltration into the myometrium. These genes encode matrix metalloproteinases, enzymes that regulate tissue remodeling, potentially contributing to the invasive nature of adenomyotic lesions.

Genetic alterations affecting hormone signaling pathways have also been implicated. Variants in ESR1, which encodes the estrogen receptor alpha, have been linked to heightened estrogen sensitivity in uterine tissue. Since estrogen drives endometrial proliferation, increased receptor activity could promote excessive tissue growth and invasion into the myometrium. A 2023 meta-analysis in The Lancet found that individuals with specific ESR1 polymorphisms had a higher prevalence of adenomyosis, reinforcing the role of genetic predisposition in hormonal influences on uterine structure.

Epigenetic modifications add complexity to adenomyosis genetics. DNA methylation and histone modifications in genes regulating inflammation and cell adhesion have been observed in affected individuals. A study in Science Translational Medicine found hypermethylation of GATA2, a transcription factor involved in endometrial cell differentiation, was significantly more common in adenomyotic tissue. This alteration may disrupt normal cellular organization, facilitating the migration of endometrial-like cells into the uterine muscle. These findings suggest inherited genetic variants set the stage for susceptibility, while epigenetic changes may trigger disease progression.

Inheritance Patterns Among Individuals

Family-based studies and twin analyses suggest adenomyosis has a genetic component, though the exact mode of inheritance remains unclear. Individuals with a first-degree relative diagnosed with adenomyosis are more likely to develop the condition. A 2022 retrospective cohort study in Human Reproduction analyzed medical records from over 10,000 patients and found a maternal history of adenomyosis increased the risk 2.3-fold.

Unlike conditions with clear Mendelian inheritance, adenomyosis appears polygenic, with multiple genes contributing to susceptibility. Genome-wide studies have not identified a single causative mutation but rather a combination of genetic variants that increase risk. A study in The American Journal of Obstetrics and Gynecology found that individuals carrying specific haplotypes within CYP19A1, which encodes aromatase (an enzyme involved in estrogen biosynthesis), were more likely to develop adenomyosis, particularly when combined with matrix metalloproteinase gene variants. This suggests hormonal and structural regulatory genes interact in disease inheritance.

Genetic penetrance appears incomplete, meaning not all individuals with predisposing genetic variants develop adenomyosis. This may be explained by gene-environment interactions, where factors such as hormonal exposure, inflammation, or mechanical stress influence disease manifestation. A study in Genetics in Medicine found that while certain genetic markers were present in affected individuals, some relatives with the same genetic profile remained asymptomatic. This suggests inherited variants contribute to risk, but their expression depends on additional regulatory mechanisms.

Molecular Mechanisms of Tissue Development

Adenomyosis results from disruptions in molecular processes governing uterine tissue organization. One key alteration involves extracellular matrix dysregulation, which affects tissue structure and cell behavior. In healthy tissue, matrix metalloproteinases (MMPs) and their inhibitors maintain balanced tissue remodeling. In adenomyosis, overexpression of MMP2 and MMP9 leads to excessive extracellular matrix degradation, weakening the boundary between the endometrium and myometrium. This structural compromise facilitates the infiltration of endometrial-like cells into the muscular layer.

Beyond extracellular matrix remodeling, aberrant cellular signaling pathways drive tissue invasion and structural changes. The Wnt/β-catenin pathway, which regulates cell proliferation and differentiation, is hyperactive in adenomyotic tissue. Elevated β-catenin levels promote unregulated cell growth, enabling endometrial-like cells to proliferate beyond their normal boundaries. Increased expression of transforming growth factor-beta (TGF-β) further enhances fibroblast activation and fibrosis, stiffening the uterine wall and contributing to chronic pelvic pain and abnormal contractility.

Hormonal imbalances exacerbate these molecular disruptions, particularly heightened estrogen signaling. Estrogen receptors, especially ERα, are more abundant in adenomyotic lesions, amplifying estrogen-driven proliferation. Additionally, aromatase, the enzyme responsible for local estrogen synthesis, is upregulated in affected tissue, creating a self-sustaining loop of estrogen production. This hormonal environment alters adhesion molecule expression, increasing cell migration and invasion into the myometrium.

Role of External Influences on Gene Expression

Environmental and lifestyle factors modify gene expression and may contribute to adenomyosis onset and progression. Epigenetic modifications, such as DNA methylation and histone acetylation, mediate these effects. Exposure to endocrine-disrupting chemicals (EDCs), found in plastics, pesticides, and personal care products, has been linked to altered estrogen receptor activity and abnormal gene expression in uterine tissue. Studies show bisphenol A (BPA) and phthalates can induce hypomethylation of estrogen-responsive genes, heightening hormonal sensitivity and potentially facilitating endometrial-like tissue infiltration into the myometrium.

Chronic exposure to elevated estrogen levels—whether from hormone replacement therapy, prolonged estrogen-based contraceptive use, or obesity-related estrogen production—can intensify these epigenetic shifts. Adipose tissue produces estrogen, and individuals with higher body fat percentages often exhibit increased aromatase activity, perpetuating estrogen-driven gene expression changes. This prolonged hormonal stimulation is associated with upregulated extracellular matrix remodeling genes, further promoting invasive tissue behavior.

Genetic Assessment in Diagnostic Procedures

Genetic research is advancing diagnostic approaches for adenomyosis. While imaging techniques like transvaginal ultrasound and MRI remain primary diagnostic tools, genetic profiling may offer additional insights into susceptibility and disease progression. Researchers are investigating whether genetic markers could support diagnosis, particularly in cases where imaging results are inconclusive or symptoms overlap with conditions like endometriosis or fibroids. By analyzing gene expression patterns in endometrial and myometrial tissue samples, clinicians may identify molecular signatures associated with adenomyosis before significant structural changes occur.

Non-invasive genetic screening methods, such as circulating cell-free DNA (cfDNA) analysis, are also being explored for early detection. Studies suggest individuals with adenomyosis exhibit distinct methylation profiles in genes related to estrogen signaling and extracellular matrix remodeling, which could be detected through blood-based assays. While still in the research phase, incorporating genetic assessment into diagnostic protocols could enhance early identification and allow for more personalized treatment strategies. As research progresses, future diagnostic tools may move beyond imaging to include molecular profiling, offering a more comprehensive approach to disease detection.