The role of TGF-β superfamily in endometriosis: a systematic review

Endometriosis (EMS) is a common chronic gynecological condition. Its hallmark is the presence of functional endometrial tissue outside the uterine cavity. This tissue is primarily located in the ovaries, peritoneum, uterosacral ligaments, rectovaginal pouch, and other areas of the body ( 1 ). The three main forms of endometriosis are superficial peritoneal endometriosis (SPE), deep infiltrating endometriosis (DIE), and ovarian endometriosis (OE) ( 2 ). In addition to causing increased localized inflammation and estrogen production, EMS affects 5–10% of women globally of childbearing age, leading to a variety of pains such as menstrual cramps, dysuria, dyschezia, and abdominal pain ( 3 ). Inflammation, cysts, scar tissue, and adhesions may lead to complications such as intestinal issues, chronic pelvic inflammatory disease, or infertility ( 4 ). Currently, Progestins, oral contraceptives, and gonadotropin-releasing hormone agonists are used to manipulate hormones to suppress menstruation and ovulation, thereby suppressing lesions. Alternatively, surgical removal of deep nodules, ovarian cysts, and peritoneal implant is employed to alleviate pain ( 5 ). However, approximately 75% of women experience a recurrence of related symptoms within two years after undergoing surgery, and medications currently used to treat EMS often have adverse side effects ( 6 ). Moreover, EMS shares biological characteristics with cancer, including dissemination, invasion, and proliferation, although clinically and pathologically presenting as benign. Recent studies have shown that progressive endometriosis may lead to endometriosis-associated ovarian cancer (EAOC), including encompassing ovarian clear cell carcinoma (OCCC) and ovarian endometrioid carcinoma (OEC) ( 6 ). The pathophysiology of EMS remains elusive, while attention to the condition has increased recently. Several studies have demonstrated differential cytokine expression in women with endometriosis, observed in serum, peritoneal fluid, and ectopic lesions. These cytokines promote endometriotic cell survival, growth, invasion, differentiation, angiogenesis, and other processes implicated in the onset and progression of endometriosis ( 7 ). The transforming growth factor β (TGF-β) superfamily is one of the cytokine families involved in endometriosis. It has been reported that TGF-β1 induced an increase in prolactin levels and significant decidual-like changes in ectopic endometrial stromal cells (ESCs). Women with mild endometriosis exhibited downregulation of progesterone receptor expression in the endometrium due to elevated levels of TGF-β1 ( 8 ). Other studies have shown that the peritoneal fluid of endometriosis cases exhibited significantly elevated levels of soluble endothelial protein, growth differentiation factor 15 (GDF-15), and TGF-β1 compared to the control group. Additionally, patients with advanced endometriosis showed significantly higher serum levels of GDF-15 compared to those in the early-stage group, suggesting a potential role for TGF-β-dependent signaling, and serum GDF-15 could serve as a potential biomarker for assessing endometriosis severity ( 9 ). To address this pervasive but still elusive pathogenesis, current research into endometriosis necessitates a comprehensive understanding of the role of cytokines in the disease. A survey of the existing literature indicates that while research on this topic has been ongoing since 1994, its scope and depth remain limited. In response to the ongoing exploration by the scientific community, it is necessary to more fully integrate TGF-β superfamily role in endometriosis, and update to the existing literature review. Therefore, this review covers both clinical findings and experimental data, offering a comprehensive summary of recent studies on the TGF-β superfamily linked to endometriosis. It is beneficial to shed light on the function of the TGF-β superfamily in the pathogenesis of endometriosis and offer fresh ideas for possible treatment approaches.

The expression levels of members of the TGF-β superfamily vary across different tissues and cells in endometriosis, depending on the stage of the menstrual cycle ( Table 2 ). Studies have consistently demonstrated that elevated TGF-β levels in the serum, glandular cells, peritoneum, and ectopic ESCs of patients with endometriosis. Moreover, activin and inhibin exhibited variable expression during the menstrual cycle and are prominently expressed in peritoneal fluid. And women with endometriosis demonstrated altered BMP-6 expression in their ovarian theca cells ( 42 ). As a multifunctional cytokine, Nodal played a key role in the biological process of ovarian endometriosis-cancerous lesions ( 43 ). Expression of TGF-βs, activin and inhibin, BMPs. Exfoliated endometrial tissue contains all three isoforms of TGF-β, which are expressed in the human endometrium in a stage-specific and cyclically regulated manner. TGF-β1 levels were significantly increased in serum, peritoneal fluid, peritoneal tissue, and ectopic endometrial tissue in patients with endometriosis compared with normal women ( 44 ). The peritoneum, particularly the peritoneal mesothelium, is a source of TGF-β1. Studies have observed that women with endometriosis had higher levels of TGF-β1 mRNA in the peritoneum at sites adjacent to endometriosis lesions compared to distant sites ( 45 , 46 ). Interestingly, one study found lower levels of TGF-β1 expression in ectopic endometrium, which may be due to post-transcriptional regulation of TGF-β1 influenced by the different microenvironments of the endometrium ( 47 ). Furthermore, TGF-β1 is found in the glandular cells, macrophages, and stromal cells of endometrial tissue ( 48 , 49 ). While both endometrial and endometriotic cells secrete TGF-β1, stromal cells secrete higher levels of TGF-β1 than epithelial cells. On the other hand, compared to normal endometrial cells, endometriotic stromal and epithelial cells secrete higher levels of TGF-β2 ( 50 ). Moreover, a clinical study reported that patients with endometriosis had higher levels of TGF-β2 in their peritoneal fluid compared to patients without the condition ( 51 ). Researchers examined the three isoforms of TGF-β in the serum and peritoneal fluid of endometriosis patients and found overall high levels of TGF-β. The level of TGF-β1 in peritoneal fluid is higher than that in serum. In both serum and peritoneal fluid, the level of TGF-β3 was the lowest compared with the other two subtypes, while the level of TGF-β2 was comparable to that of TGF-β1 ( 52 ). During the menstrual cycle, three distinct expression profiles were observed. TGF-β1 shows a slight increase during the menstrual phase and remains relatively stable thereafter. It maintains a baseline level of regulation throughout the cycle, which ensures essential cellular functions such as proliferation and apoptosis. TGF-β2 exhibits a sharp five-fold increase from the early secretory phase to the secretory and menstrual phases, followed by a rapid five-fold decrease from the menstrual to the proliferative phase. This indicates a tightly regulated temporal expression of TGF-β2, which is crucial for the cyclical changes the endometrium undergoes. TGF-β3 mRNA levels increase threefold from the secretory phase to the menstrual phase and remain elevated throughout the proliferative phase. It likely contributes to the regulated proliferation and migration of endometrial cells, ensuring the proper reconstruction of the endometrial lining after menstruation ( 53 ). The various isoforms of TGF-β throughout the menstrual cycle underscore their specialized and potentially complementary roles in regulating endometrial physiology. Understanding these patterns can provide deeper insights into the complex regulatory mechanisms governing endometrial function, potentially opening new avenues for therapeutic interventions in conditions such as EMS and infertility. An earlier study showed that the expression levels of the hormones inhibin A, inhibin B, and activin A were elevated in the peritoneal fluid of endometriosis patients throughout the menstrual cycle ( 54 ). Subsequent studies have shown that the concentrations of inhibin A and activin A in the cystic fluid of ovarian endometriosis patients were significantly higher than in peripheral blood, and slightly higher than those in the peritoneal fluid. This indicates that inhibin A and activin A are produced locally in ovarian endometriosis ( 55 ). Activin βA and follicular inhibitory mRNA are also discovered to be locally expressed in the human endometrial epithelium. Follicular inhibin does not significantly increase during the secretory phase, while activin A is expressed by endometrial epithelial and stromal cells, and increases during this phase ( 56 ). Other studies showed that women with EMS exhibited higher levels of follicular inhibin mRNA expression during the secretory phase compared to the proliferative phase. Thus, malfunction of the activin pathway in EMS may contribute to the aberrant expression of follicular inhibin ( 57 ). However, serum levels of follicular inhibin are significantly elevated in women affected by endometriosis, distinguishing it from other benign ovarian cysts ( 58 ). Due to its sensitivity and specificity, follicular inhibin is expected to serve as a valuable clinical marker for ovarian endometriosis. On the other side, it was demonstrated that there were no significant changes in serum activin A and follicular inhibin in SPE and DIE, suggesting low diagnostic accuracy for OE ( 59 ). In a recent study, ectopic ESCs and peritoneal fluid from EMS patients were found to have a markedly higher expression of follicle suppressor-like I (FSTL1) compared to normal controls. This increase offered a fresh viewpoint on the genesis of EMS and could be the result of increased angiogenesis and proinflammatory factor secretion ( 60 ). The increased expression of follicostatins suggested that it could be a novel target for future treatments and a potential diagnostic indicator for EMS. Later on, it was demonstrated that through experimental methods the activin signaling system was present in both ovarian endometriosis and normal endometrium, and that both conditions produced activin A rather than inhibin ( 61 ). Activin βA mRNA is predominantly expressed in stromal cells, exhibits lower expression in epithelial cells, and demonstrates increased expression during the secretory phase of the menstrual cycle. Conversely, both stromal and epithelial cells exhibited negligible levels of inhibin α mRNA ( 62 ). In the same investigation, metaphase stromal cells exhibited low levels of inhibin α expression and high levels of activin βA expression. Activin promotes the differentiation of extravillous trophoblasts (EVTs) and the secretion of MMP-2 during trophoblast invasion. MMP-2 production in the immobilized EVT population decreases concomitantly with an increase in inhibin in the intravascular trophoblasts, indicating strong immunoreactivity between activin and inhibin. Accordingly, maternal tissue transformation is the primary source of activin, which is involved in both trophoblast invasion and tissue remodeling. In contrast, it is possible that inhibin may reduce trophoblast invasion ( 62 ). The study demonstrated for the first time that the human endometrium expresses Nodal and Cripto, in addition to activin A and its receptor. This discovery expands the list of genes associated with activin that are known to be locally expressed in the endometrium and raises the possibility that endometrial abnormalities in women affected by endometriosis are influenced by the activin system ( 63 ). In endometriosis women, ectopic endometrium during the secretory phase may exhibit decreased inhibin α and increased follicular inhibitor mRNA expression, alongside impaired activin A expression. This impaired ecdysis could potentially affect embryo implantation ( 55 ). At every stage of the menstrual cycle, whether it is the proliferative or secretory phase, the healthy endometrium expresses mRNA for the muscle growth inhibitor and the inhibitor of inhibition ( 29 ). Some studies have found that the glandular epithelium and stroma of the endometrium contained inhibin α and its co-receptor β-glycan. Women affected by endometriosis exhibited aberrantly elevated expression of β-glycan and inhibin α mRNA during the secretory phase. However, it remained unclear whether endometriosis itself was the cause of these abnormal expressions ( 64 ). The stroma and epithelium of the ectopic endometrium both exhibit high levels of expression of bone morphogenetic protein 6 (BMP6). Also BMP6 expression contributes to the formation of an estrogen-rich microenvironment and is strongly correlated with the high expression of estrogen receptor alpha ( 65 ). Granulosa cells (cumulus cells) affected by endometriosis exhibit elevated follicle-stimulating hormone levels during the proliferative phase, while BMP15 expression is inhibited ( 66 ). And BMP6 expression is downregulated in the cumulus cells of endometriosis women ( 42 ). The concentration of BMP2 in the peritoneal fluid of endometriosis women is lower than that in healthy women ( 67 ). This finding may negatively impact the process of ecdysis in these women, potentially causing issues with conception and pregnancy. Moreover, endometriosis patients show a higher concentration of BMP7 in the peritoneal fluid. This may be due to heavy menstrual bleeding associated with increased expression of genes encoding BMP7 molecules ( 67 ). Other studies have shown that the expression of BMP7 in the endometrium of endometriosis patients is significantly increased, and the expression reaches its peak in both the proliferative and secretory phases ( 68 ).

BMP is a multifunctional extracellular growth factor involved in various cellular processes ( Figure 3 ). Both the endometrial and maternal-fetal interfaces express BMP ligands, receptors, and associated transduction molecules. BMP signaling plays a crucial role in modulating the interactions between endometrial and maternal-fetal tissues. These interactions are essential for successful implantation and the maintenance of pregnancy. Dysregulation of BMP ligands, their receptors, or associated signaling pathways can lead to altered endometrial remodeling, potentially resulting in obstetrical complications or infertility. In other words, the process of metamorphosis is influenced by BMPs. Among these, BMP2 is a growth factor that plays a critical role in this process ( 126 ). In individuals with endometriosis, decreased BMP signaling was found to hinder endometrial metamorphosis. This impairment in signaling disrupts the normal cellular and tissue transformations necessary for a healthy endometrial environment. BMP2 supplementation increases the capacity for metamorphosis in stromal cells and endometrial assemblies of these patients. It shows that BMP2 plays a crucial role in enhancing cellular and tissue transformations ( 127 ). A variety of cell types, including pericytes that support the neovascular basement membrane structure, are regulated in terms of proliferation and differentiation by the pleiotropic BMP2 signaling molecule ( 67 ). Women affected by endometriosis had lower concentrations of BMP-2 in their peritoneal fluid. This reduction disrupted the normal structure of blood vessels and encouraged the development of endometrial fibrosis and adhesions. In the same study, increased concentrations of BMP-7 were found to control menstrual bleeding. This regulation, in turn, encouraged the development of endometrial implants ( 67 ). Overall, the formation of the endometrium appears to be influenced by both BMP-2 and BMP-7. Previous studies showed that BMP-6 was highly expressed in endometriosis. This elevated expression suggests a potential role for BMP-6 in the pathophysiology of endometrial disorders ( 65 ). Subsequent research found that the expression of BMP-6 and SMAD4 was reduced in women with peritoneal endometriosis. Additionally, it was found that granulosa cell function may be altered in women with endometriosis, potentially affecting their fertility ( 42 ). The BMP7-SMAD4-CDH1 signaling pathway may be negatively regulated by miR-542-3p. CDH1 mRNA transcripts, as well as SMAD4 and BMP7 mRNA transcripts, were down-regulated. Conversely, the expression of miR-542-3p was highly elevated. According to these results, women with endometriosis do not exhibit the typical endometrial epithelial phenotype. This finding supports the hypothesis that alterations in epithelial characteristics play a significant role in the etiology of endometriosis ( 68 ).

The objective of this systematic review is to investigate the TGF-β superfamily, with a particular focus on how TGF-β, activins, statins, and bone morphogenetic proteins (BMPs) contribute to the development and maintenance of endometriosis lesions. According to the recommendations of the Preferred Reporting Project for Systematic Review and Meta-Analysis (PRISMA) guidelines ( 10 ), a literature search was conducted in the PubMed and Web of Science database to systematically review the primary research articles published up to April 30, 2025 using the following search terms: “endometriosis” AND “TGF-β” or “endometriosis” AND “BMP” or “endometriosis” AND “activin” or “endometriosis” AND “inhibin” or “endometriosis” AND “GDF-8” or “endometriosis” AND “nodal” or “endometriosis” AND “AMH”. All authors jointly formulated and agreed on the inclusion and exclusion criteria. Studies that met the following criteria included: (a) English articles; (b) Original full-text articles; (c) To focus on the role of TGF-β superfamily in EMS. In addition, the citations of the identified studies were reviewed to incorporate more relevant articles. The exclusion criteria included: (a) Non-English articles; (b) Non-original research articles; (c) Withdrawn publications; (d) No full manuscripts available; (e) No direct relationship with TGF-β or EMS. Finally, a total of 61 articles were included in the review ( Supplementary Figure S1 , Supplementary Table S1 ).

The possible involvement of endometrial MSCs in endometriosis has also been a significant area of recent study. Stem cell therapy is considered a cutting-edge therapeutic approach for treating fibrosis and uterine adhesions. This innovative treatment has shown potential in regenerating damaged tissues and improving uterine function. Studies have shown that TGF-β1 is secreted by endometrial MSCs which are a pro-fibrotic factor that stimulates the fibrotic process in endometriosis. This stimulation occurs through pathways such as Wnt/β-catenin or SMAD3/DNMT3A ( 7 , 114 ). But the correlation between the two remains unclear. Furthermore, miRNAs impact the EMT and the TGF-β signaling pathway. These interactions in turn influence the development of endometriosis. miRNAs also impact the proliferation, apoptosis, migration, and invasion of endometriotic stromal cells. Therefore, a thorough understanding of TGF-β superfamily members and their interactions with different pathways is necessary to fully realize their therapeutic potential. In the future, these targets might become viable therapeutic objectives for treating endometriosis. So far, several medications have been discovered to influence TGF-β expression and reduce the size of endometriotic lesions in endometriosis ( Table 3 ). For instance, kiwi root extract regulated TGF-β expression in endometriotic lesions by downregulating VEGF-A via TGF-β1, and prevented neovascularization in endometriosis ( 140 ). Resveratrol exhibited antioxidant, anti-inflammatory, and anti-angiogenic properties. It could enhance the advancement of endometriosis by reducing TGF-β expression in ESCs. However, further investigation was required to determine the precise mechanism of action ( 128 ). Cannabidiol impacted endometriosis by inhibiting fibrosis and downregulating TGF-β expression in rat endometriotic cells ( 129 ). Fisetin reduced fibrosis in endometriotic lesions and decreases TGF-β expression in endometriotic cells ( 101 ). Salbutamol could lower the expression of TGF-β in lesions and lessen the content of collagen fibers, showing an obvious inhibitory effect on fibrosis ( 141 ). These studies suggest that TGF-β-targeting medications may be used to treat endometriosis. Notably, our understanding of the precise mechanism of action of these agents is limited. Future research should focus on their relevant mechanisms to explore more clinical potentials. Therapeutic effects of drugs on EMS via TGF-β. Additionally, the search for TGF-β-based treatment strategies for pathologies sharing key features with endometriosis may bring new insights. For instance, fibrosis is an important pathological feature of all types of endometriosis. Meanwhile, it is also a common pathological feature of pulmonary fibrosis, liver fibrosis, kidney fibrosis, systemic sclerosis and other fibrotic diseases, and is closely related to the occurrence of a variety of tumors ( 144 ). TGF-β stimulates the activation and proliferation of fibroblasts, leading to extracellular matrix deposition. Its increased expression can cause many fibrotic diseases, and its expression level is often related to the severity of the disease. Researchers have developed different strategies to regulate the activity of TGF-β based on its molecular mechanisms of signaling and activity, including TGF-β -targeted antibodies, small molecule receptor inhibitors, ligand traps, antisense oligonucleotides, etc ( 145 ). These results may be crucial for future development of targeted TGF-β therapy for endometriosis.

This study provided a comprehensive review of the role of TGF-β superfamily in endometriosis. The relationship between TGF-β, activin, inhibin and BMP and endometriosis was discussed, and the signal transduction and expression of these factors in endometrium were summarized. TGF-β can stimulate the adhesion, invasion and proliferation of ESCs, affecting the occurrence of endometriosis. It also plays a role in the development of fibrosis in the focal tissue of endometriosis, and suppresses the immune response. However, the precise function of TGF-β in controlling blood vessels still needs to be further clarified. Current knowledge about the involvement of TGF-β superfamily members in endometriosis underscores the great potential and complexity of this field. It underscores the necessity for comprehensive investigation into the involvement of TGF-β superfamily members in endometriosis. This includes their effects on endometrial metaplasia, focal tissue fibrosis, and cell migration and proliferation. To fully realize the potential of TGF-β superfamily members in clinical therapies, their complex roles in endometriosis should be continuously explored and elucidated.