{"paper_id":"d0596f26-5edc-4fae-a794-70e2ed6312b6","body_text":"Review\n8\nCopyright© 2025 The Author. Published by Galenos Publishing House on behalf of National Society of Gynecology and Obstetrics. This is an open \naccess article under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 (CC BY-NC-ND) International License.\nThe Importance of Exosomes in Gynecological Diseases \n Naci Çine,  Hakan Savlı\nKocaeli University Faculty of Medicine, Department of Medical Genetics, Kocaeli, Turkey\nExosomes play significant roles in key functions of the female reproductive system, such as oogenesis, implantation success, \nembryo development, and proper fertilization. Functional connectivity between cells is essential for the viability , development, \nand coordination of the female reproductive system. It has been demonstrated that the information carried by exosomes is \ncrucial for these cooperative biological mechanisms.\nExosomes are formed and encapsulate biological molecules from the cells of origin. They contribute both to the reorganization \nof cellular functions and to the collective functioning of cell populations. In addition the content of exosomes may be used to \nmonitor the diagnostic and therapeutic processes of various gynecological diseases. They contain genetic and proteomic data \nthat can be used as biomarkers or therapeutic targets in gynecological cancers and pregnancy-related disorders.\nThis article will review the roles of exosomes in major female reproductive disorders, including endometriosis, premature ovarian \nfailure, polycystic ovary syndrome, Asherman syndrome, endometrial cancer, cervical cancer, ovarian cancer, and preeclampsia.\nKeywords: Exosomes, infertility . women’s reproductive diseases\nABSTRACT\nINTRODUCTION\nExosomes are extracellular vesicles secreted by cells \nand possess a double-layered lipid membrane. 1-3 These \nvesicles typically measure between 30-150 nm in diameter. 4 \nTheir contents include RNA molecul es, proteins, lipids, \nand occasionally DNA. 5-7 These components regulate \nvarious cellular functions mediated by exosomes. 8 Based \non size, surface markers, biogenesis, and content, three \nmajor types of extracellular vesicles are recognized: \napoptotic bodies, microvesicles, and exosomes. 9,10 \nExosomes are effective paracrine regulators of intercellular \ncommunication. In recent years, they have been \nshown to participate in biological functions including \nmetabolic regulation, cell proliferation, apoptosis, \nangiogenesis, antigen presentation, inflammation, \ntumor pathogenesis, tissue repair, and reproduction. 11-13 \nExosomes are produced through the inward budding of \nendosomal membranes, forming multivesicular bodies, \nwhich later fuse with the plasma membrane to release \nexosomes.14 They interact with target cells via ligand-receptor \nbinding or endocytosis. 15 Following this interaction, vesicles \nare internalized by phagocytosis. 2,16 Functional protein \ngroups found in exosomes include β-actin, GPI-anchored \nproteins, heat shock proteins (HSP8, HSP90), tubulin, and \ntetraspanins such as CD9, CD63, and CD8. 17 Under both \nphysiological and pathological conditions, exosomes reflect \nthe molecular characteristics of their donor cells. This makes \nthem valuable prognostic and diagnostic biomarkers. 18,19 \nExosomes are be secreted from various tissues of the female \nreproductive system, including the fallopian tube epithelium, \nfollicular fluid, endometrium, uterus, and placenta. 20-23 \nProper reproductive function and successful pregnancy rely \nheavily on effective intercellular communication. Oogenesis, \nfollicular development, implantation, fertilization, and embryo \ndevelopment are closely tied to maternal-embryo cellular \ninteraction during pregnancy. 13,24,25 Studies have confirmed \nboth direct and indirect roles of exosomes in cellular \ncommunication.26-28\nExosomes communicate with recipient cells through \ndelivery of the exosomal contents .29-31 Once exosomes \nare internalized, they initiate physiological processes by \nAddress for Correspondence: Naci Çine, Kocaeli University Faculty of Medicine, Department of Medical Genetics, Kocaeli, Turkey \nE-mail: nacicine@yahoo.com ORCID ID: orcid.org/0000-0001-9063-1073\nReceived: 26.04.2025 Accepted: 05.05.2025 Publication Date: 29.05.2025\nCite this article as: Çine N, Savlı H. The importance of exosomes in gynecological diseases. Anat J Obstet Gynecol Res. 2025;2(1):8-15\nDOI: 10.4274/anajog.galenos.2025.83007\nAnat J Obstet Gynecol Res 2025;2(1):8-15\n\nAnat J Obstet Gynecol Res 2025;2(1):8-15Çine and Savlı. Exosomes in Gynecological Diseases\n9\ndelivering bioactive molecules such as coding and non-\ncoding RNAs, proteins, and lipids. These molecules \nmodulate the functions of the recipient cells. 32-34 \nStudies in human and animal models have demonstrated \nthat exosomes are involved in follicular development, oocyte \nmaturation, and embryo formation. They are also known to \ncarry microRNAs (miRNAs) involved in meiotic resumption \nand ovulation signaling pathways. 35 miRNAs are non-coding \nRNAs composed of 21-24 nucleotides and participate \nin various biological processes. They regulate oocyte \ndevelopment, follicular growth, implantation, and embryo \ndevelopment by targeting key genes. 36 The most common \nsignaling pathways by miRNAs include Wnt (Wingless), \nneurotrophin, epidermal growth factor receptor (EGFR), \nand transforming growth factor-beta (TGF-β) pathways. 37-39 \nResearch into the roles of exosomes in reproductive disorders \nis expanding rapidly. Due to their diagnostic and therapeutic \npotential, exosomes are anticipated to play an increasingly \nsignificant role in future gynecological disease management.40 \nThis review focuses on the implications in polycystic ovary \nsyndrome (PCOS), premature ovarian failure (POF), Asherman \nsyndrome, endometriosis, endometrial cancer, cervical cancer, \novarian cancer, and preeclampsia.\nPolycystic Ovary Syndrome \nPCOS is an endocrine disorder characterized by \novulatory dysfunction and hyperandrogenism. Affecting \n6-8% of women globally, PCOS is associated with \ninfertility, obesity, insulin resistance, dyslipidemia, \ntype 2 diabetes, and cardiovascular diseases. 41-45 \nFollicular fluid analyses from PCOS patients revealed \nincreased expression levels of miR-25-3p, miR-126-3p, \nmiR-143-3p, miR-146a-5p, miR-193b-3p, miR-199a-5p, \nmiR-199a-3p, miR-199b-3p, miR-629-5p, miR-4532, miR-\n4745-3p, and miR-6087. In addition, elevated levels of miR-\n10a-5p, miR-18a-3p, miR-20b-5p, miR-23b-3p, miR-98-5p, \nmiR-106a-5p, miR-141-3p, miR-200a-3p, miR-200c-3p, \nmiR-382-5p, miR-483-5p, miR-483-3p, and miR-3911 were \nobserved. Changes in tRNA and piRNA expression patterns \nwere also noted in exosomes derived from PCOS patients.46-48 \nThese miRNA alterations are implicated in the mitogen-\nactivated protein kinase signaling pathway, circadian \nrhythm regulation, endocytosis, and overall PCOS risk. 46-\n48Another study reported increased expression of S100-A9 \nin the exosomes of PCOS patients. 49 S100-A9, a calcium-\nbinding protein secreted by ovarian, granulosa, and immune \ncells, is involved in cell cycle regulation, proliferation, and \ninflammation.50,51 These exosomes were shown to activate \nthe NF-κB signaling pathway in granulosa-like tumor cells and \nelevate pro-inflammatory factor expression.49 This inflammatory \nmechanism may underlie reproductive dysfunction in PCOS.41,49 \nIn addition to their diagnostic value, exosomes may offer \ntherapeutic benefits. For instance, exosomes derived from \nadipose mesenchymal stem cells (MSCs) alleviated PCOS \nsymptoms by inhibiting apoptosis via miR-323-3p and altering \nPDCD4 expression.52 \nPremature Ovarian Failure\nPOF is an infertility disorder characterized by \nhypergonadotropism, amenorrhea, and estrogen deficiency \ndue to follicular dysfunction. It affects approximately 1% \nof women aged 30-39 years. 53-55 While its etiology remains \nunclear, POF is considered a heterogeneous condition \ninfluenced by both genetic and environmental factors. 56 \nRecent studies have investigated the therapeutic potential \nof exosomes in POF . For example, exosomes derived from \nplacenta-derived (PD)-MSCs increased the expression of \nantioxidant enzymes such as catalase and peroxiredoxin \n(PRDX1) in ovariectomized rats, improving ovarian function \nand reducing mitochondrial reactive oxygen species levels.  \nSimilarly, human amniotic epithelial cell-derived exosomes \ncontaining miR-1246 were found to restore ovarian \nfunction in POF mice via modulation of apoptosis- and \nphosphatidylinositol-related pathways. 57 Exosomes derived \nfrom various MSCs also improved follicular morphology and \nsuppressed apoptosis through miR-664-5p, targeting p53. 58 \nAnother study demonstrated that bone marrow-derived MSC \n(BMSC) exosomes containing miR-144-5p targeted PTEN, \ninhibited apoptosis, and improved ovarian function in POF \nrats.59 Collectively, these studies suggest that exosome-\nbased therapy could represent a promising approach for the \ntreatment of POF .\nAsherman Syndrome\nAsherman syndrome is characterized by intrauterine \nadhesions caused by trauma, leading to hypomenorrhea \nand infertility. 60 These scar tissues obstruct blastocyst \nimplantation and result in infertility. Although surgical \nintervention is commonly used to treat this condition, \nalternative therapeutic strategies are still required. 61,62 \nRecent studies suggest that exosomal therapy could be \nbeneficial in Asherman syndrome. In a rat model, MSC-\nderived exosomes were shown to reduce fibrosis and \npromote proliferation and vascularization in uterine tissue. \nFollowing exosome application, gene expression levels of \nmatrix metalloproteinases MMP-2 and MMP-9, proliferating cell \nnuclear antigen, CD31, and vascular EGFR were increased, \nwhile tissue inhibitor of metalloproteinase-2 levels decreased. \nThese findings suggest that exosomes could be promising \nbiomolecules for treating Asherman syndrome.\nEndometriosis\nEndometriosis is a multifactorial, estrogen-dependent \ndisorder characterized by the presence of endometrial \ntissue outside the uterine cavity. The main clinical \nmanifestations include pelvic pain and infertility. 64-66 \nCurrently, no definitive treatment ensures the complete \nresolution of symptoms or long-term remission. 67,68 \nExosomes have emerged as both therapeutic agents and \nbiomarkers for understanding the pathophysiology of \nendometriosis. Some studies have identified novel diagnostic \ntargets, while others suggest therapeutic roles for exosomes.  \n\nAnat J Obstet Gynecol Res 2025;2(1):8-15Çine and Savlı. Exosomes in Gynecological Diseases\n10\nExosomes derived from the endometrium have contributed \nsignificantly to elucidating the underlying mechanisms \nof endometriosis. In one study, exosomes isolated from \nperitoneal fluid samples of patients with endometriosis \ncontained histone type 2-C, PRDX1, inter-α-trypsin inhibitor \nheavy chain H4, annexin A2, and tubulin α-chain. 69 \nAnother study examining tissue and plasma-derived \nexosomes from endometriosis patients reported significant \ndifferences in miRNA and lncRNA profiles. Decreased \nexpression was noted in lncRNAs LINC00293, LINC00929, \nMEG8, SNHG25, and RP5-898J17.1, while increased \nexpression was observed in LINC00998, NEAT1, PVT1, H19, \nand RP4-561L24.3. These RNA molecules influence signaling \npathways associated with angiogenesis and inflammation. 70 \nExosomal miRNAs, including miR-130b, miR-145, miR-342, \nmiR-365, miR-425, miR-432, miR-451a, miR-486-5p, miR-505, \nmiR-1908, miR-4488, and miR-6508 have shown significant \nassociations with inflammatory processes in endometriosis. 71 \nA recent study proposed that elevated serum levels \nof exosomal miR-22-3p and miR-320a could serve as \ndiagnostic markers for endometriosis. 72 These findings \nhighlight the potential of exosomes in improving diagnostic \naccuracy and developing novel treatment approaches.  \nAnother essential feature of exosomes is their therapeutic \npotential. Exosomes from healthy endometrial epithelial \ncells carry molecules important for embryo-endometrial \ninteraction during implantation. 72 Application of these \nexosomes in endometriosis models has shown beneficial \neffects in modulating the ectopic endometrial environment.73-76 \nProteins such as focal adhesion kinase and various surface \nreceptors have been shown to influence the adhesive and \nmigratory capacities of trophoblast cells via exosomal \nsignaling.77 miRNAs, including miR-17, miR-30d, miR-\n106a, and miR-200c were found to play critical roles in \nimplantation success when transferred by exosomes. 29,78,80 \nM2 macrophage-derived exosomes exhibit regenerative \nproperties that may reduce endometriotic lesions. These \nexosomes, which are underrepresented or altered in patients \nwith endometriosis, contribute to macrophage activation \nmediated by miR-223. 81,82 Wu et al. 83 demonstrated that miR-\n214 suppresses fibrosis and promotes lesion regression.  \nCollectively, these studies suggest that exosomes may \nmodulate immune escape, cell proliferation, angiogenesis, \nand lesion invasion in endometriosis. Exosomes derived \nfrom ectopic or shed endometrial tissue might also induce \nmetaplasia or tissue repair in recipient cells through the \nmiRNAs and specialized proteins they carry.84\nEndometrial Cancers\nEndometrial cancer is the fourth most common malignancy of the \nfemale reproductive system.85 While most cases are diagnosed \nearly due to postmenopausal bleeding, approximately 20% \nare identified at an advanced stage. 86,87 Surgical procedures, \nradiotherapy, and chemotherapy are commonly employed \nin treatment, but these approaches are often insufficient. \nTherefore, identifying new molecular targets and biomarkers \nis important for more effective disease management.  \nExosomes play important roles in the pathogenesis, \nprogression, diagnosis, and potential treatment of endometrial \ncancer. Communication between endometrial fibroblasts \nand cancer cells via exosomes has been proposed. 88 In one \nstudy, exosomes derived from cancer-associated fibroblasts \nlacked miR-148b, contributing to tumor progression. Under \nnormal conditions, miR-148b suppresses DNA (cytosine-\n5)-methyltransferase 1, a protein involved in metastasis by \npromoting epithelial-mesenchymal transition. 89 The absence \nof miR-148b in CAF-derived exosomes is believed to drive \nendometrial cancer progression through this mechanism.  \nFurthermore, exosomes isolated from the plasma of \nendometrial cancer patients were shown to promote \nangiogenesis in human umbilical vein endothelial cells \nby activating the PI3K/AKT/VEGFA signaling pathway. 90 \nmiR-320a, which targets hypoxia-inducible factor 1-alpha, \nnormally suppresses VEGFA expression and cell proliferation. \nHowever, reduced levels of miR-320a in CAF-derived \nexosomes may facilitate malignancy in endometrial cancer. 91 \nExosomes from the serum of PCOS patients have been reported \nto enhance the migration and invasion of endometrial cancer \ncells via upregulation of miR-27a-5p, which targets SADM4. 92 \nIn another study, 114 dysregulated miRNAs were \nidentified in exosomes isolated from peritoneal lavage \nfluid of endometrial cancer patients. Notable miRNAs \nincluded miR-10b-5p, miR-34b-3p, miR-34c-5p, miR-34c-\n3p, miR-449b-5p, miR-200b-3p, miR-383-5p, and miR-\n2110, all of which were proposed as novel biomarkers. 93 \nThese studies suggest the potential importance of exosome-\nderived data in endometrial cancer research. Furthermore, they \nindicate that the sample type and cellular origin of exosomes \nmay be critical for accurate diagnosis and effective therapeutic \ntargeting. The biological source of exosomes may influence \ntumor behavior, highlighting the need for careful evaluation of \nexosome origin in both research and clinical applications.\nCervical Cancer\nCervical cancer originates from squamocolumnar junction \ncells of the cervix and is closely associated with human \npapillomavirus infection. 94,95 Early diagnosis, as in many \ncancers, is important for preventing disease progression \nand improving outcomes. 96 Consequently, identifying novel \nbiomarkers for early detection is of great clinical significance.  \nExosomal miRNAs have been shown to be associated with \nthe progression of cervical cancer. Increased expression \nlevels of miR-21, miR-146a, miR-221-3p, miR-222, let-\n7d-3p, and miR-30d-5p were found in cervical lavage \nsamples and cell lines, while plasma levels of miR-125a-\n5p were decreased in cervical cancer patients. 97-102 \nAmong these, miR-221-3p has been identified as a key \nregulator of angiogenesis through its modulation of the \nthrombospondin-2 gene. 103 These findings support the \nuse of exosomal miRNAs and other molecules as potential \ndiagnostic and therapeutic biomarkers for cervical cancer.  \nMoreover, exosomes derived from cervical cancer cell lines \nhave been found to carry high levels of miRNAs targeting \nHedgehog signaling pathway components such as PTCH1, \nsmoothened, frizzled family receptor, sonic hedgehog \nsignaling molecule, Indian hedgehog signaling molecule. This \n\nAnat J Obstet Gynecol Res 2025;2(1):8-15Çine and Savlı. Exosomes in Gynecological Diseases\n11\npathway is implicated in cervical cancer growth, metastasis, \ninvasion, and drug resistanc. 104 Exosome-based analysis of \nthis pathway may help identify novel therapeutic agents that \ncan inhibit Hedgehog signaling and halt disease progression. \nOngoing research has also demonstrated the potential of \nexosomes as therapeutic agents. For example, exosomes \nenriched with miR-22 have shown a positive effect on \nradiotherapy efficacy by downregulating c-Myc binding \nprotein (MYCBP) and human telomerase reverse transcriptase \n(hTERT) gene expression.105 Given the molecular cargo carried \nby exosomes, they may hold potential for contributing to both \ndiagnosis and therapy in the management of cervical cancer.\nOvarian Cancer\nOvarian cancer is the most lethal gynecological \nmalignancy and ranks among the most prevalent cancers \naffecting the female reproductive system. 106 More than \n50% of patients are diagnosed at an advanced stage, \ncontributing to a five-year survival rate of less than 50%. 85,107 \nThe poor prognosis and quality of life among ovarian cancer \npatients are partly attributed to the absence of effective \nearly diagnostic tools. Thus, the development of novel \ndiagnostic and therapeutic strategies will be beneficial \nfor identifying cases earlier and improving outcomes. 108 \nExosomes secreted by ovarian cancer cells have been shown \nto play significant roles in tumor progression, metastasis, \nand invasion. Exosomal proteins such as TSG101, CD9, \nCD24, CD44, and CD63 contribute to the development of \novarian cancer by facilitating intercellular communication.  \nMolecules like HSP27, HSP70, and HSP90 are highly \nexpressed in ovarian cancer patients and are involved \nin disease pathogenesis. 109-113 Enzymes, such as \naldehyde reductase, phosphoglycerate isomerase, \nfatty acid synthase, and PRDX1, together with major \nhistocompatibility complex class I and II have also been \nassociated with tumor development and metastasis 108,114. \nIn addition to their roles in tumor biology, exosomal proteins \nare involved in drug resistance. Elevated levels of annexin A3 in \nexosomes has been linked to increased platinum resistance in \novarian cancer cells.115 Exosomal miRNAs including miR-106a, \nmiR-130a, miR-221, miR-222, miR-433, and miR-591 have \nalso been associated with drug resistance mechanisms. 116-120 \nExosome-associated miRNAs miR-21, miR-184, miR-\n193b, miR-200a, miR-200b, miR-200c, miR-203, miR-\n214, and miR-215 have shown potential as diagnostic \nbiomarkers for ovarian cancer. 112,114,121-123 Additional \nmiRNAs including miR-25, miR-29b, miR-100, miR-105, \nmiR-150, miR-187, miR-221, and miR-335 are implicated \nin the development of malignant ovarian tumors. 112,114,124 \nNotably, miR-21 has emerged as a critical player in oncogenesis \nand metastasis in serous ovarian carcinoma, functioning \nas an oncomiR. 125 Moreover, exosome-delivered molecules \nhave therapeutic potential. For instance, miR-29c, miR-101, \nmiR-128, miR-182, miR-506, and miR-520d-3p are under \ninvestigation as possible treatment targets for ovarian cancer.126 \nTogether, these studies suggest that non-coding RNAs and \nproteins delivered via exosomes may play important roles \nin the biology, diagnosis, and treatment of ovarian cancer. \nGaining a better understanding of the mechanisms through \nwhich exosomes influence ovarian cancer progression could \npotentially contribute to the development of more effective \ntherapies and improved disease management.\nPreeclampsia\nPreeclampsia is a hypertensive disorder of pregnancy \nresponsible for 10-15% of all fetal deaths. It is associated \nwith significant maternal and fetal morbidity and typically \noccurs after the 20 th week of gestation. The condition is \noften characterized by placental hypoxia. 127-130 Despite \nconsiderable research, the molecular mechanisms \nunderlying preeclampsia remain unclea. 131-133 \nRecent evidence suggests that exosomes released by \nplacental trophoblasts into maternal circulation may contribute \nto the pathogenesis of preeclampsia.134 Hypoxic conditions in \nthe placenta are known to increase the release of exosomes \nfrom the syncytiotrophoblast layer. 135,136 Therefore, analyzing \nthe contents of PD exosomes may help to understand \ndisease pathogenesis and improve diagnostic capabilities.  \nIncreased levels of syncytin a protein involved in the \ndifferentiation of syncytiotrophoblasts from villous \ntrophoblasts, have been found in the exosomes of \npreeclamptic patients. These trophoblasts play a key role \nin remodeling maternal spiral arteries and differentiating \nvascular endothelial and smooth muscle cells. 137-139 \nExosomal profiling in preeclamptic patients revealed that miR-\n23a-3p, miR-125b-2-3p, miR-144-3p, miR-192-5p, miR-205-5p, \nmiR-208a-3p, miR-335-5p, miR-451a, miR-518a-3p, and miR-\n542-3p were downregulated. In contrast, miR-7a-5p, miR-\n17-5p, miR-26a-5p, miR-30c-3p, miR-141-3p, miR-199a-3p, \nmiR-221-3p, miR-584-5p, miR-744-5p, and miR-6724-5p were \nupregulated.140-143\nSafety of Exosomes\nExosomes have been shown to distribute into all body \ncompartments bypassing blood-brain barrier, blood testis \nbarrier and blood follicle barriers. 144-146 This suggests a novel \nuse for exosomes as drug delivery agents. This is in addition \nto their potential as diagnostic agents in different diseases \nand direct use as therapeutic agents. Specific tissue cell \nculture exosomes were classified as enhanced exosomes \nwhile natural in vivo produced exosomes from stem cells \ncan be classified as naive exosomes. 147 Naive exosomes are \nmostly obtained from human umblical cord stem cells, human \numblical cord blood stem cells, human and human induced \npluripotent stem cell derived MSCs. 148 Exosomes were not \nreported to cause immunologic reactions and can be applied \nto the area of inflamation. 149 Exosomes were not shown to \nform teratomas in contrast to some stem cell therapie.150\nAdvences in technology are driving progress in the \ndiagnostic and therapeutic strategies for gynecological \ndiseases. However, new approaches are still needed to \naddress the complexities of these conditions. Research \nsuggests that exosomes offer promising potential in \ngynecological disorders by providing new mechanism s \nfor diagnosis, treatment, and disease monitoring.  \nExosome-based studies are expected to make substantial \n\nAnat J Obstet Gynecol Res 2025;2(1):8-15Çine and Savlı. Exosomes in Gynecological Diseases\n12\ncontributions to understanding and managing gynecological \ndiseases, particularly through the identification of novel \ndiagnostic markers and therapeutic targets, and improved \npatient monitoring strategies.\nFootnote\nAuthorship Contributions \nLiterature Search: N.Ç., H.S., Writing: N.Ç., H.S.\nConflict of Interest: No conflict of interest was declared by \nthe authors. \nFinancial Disclosure: The authors declared that this study \nreceived no financial support. \nREFERENCES\n1. Cocucci E, Racchetti G, Meldolesi J. Shedding microvesicles: \nartefacts no more. Trends Cell Biol. 2009;19(2):43-51. \n2. EL Andaloussi S, Mäger I, Breakefield XO, Wood MJ. 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