{"paper_id":"c425cf38-1357-40b3-bac4-ec233b4869fc","body_text":"1047\nAvailable online at www.medicinescience.org\nORIGINAL ARTICLE\nMedicine Science 2025;14(4):1047-53\nMedicine Science \nInternational\nMedical Journal\nIntroduction\nThe uterine lining's aberrant growth on the outside of the uterus \nand associated organs is a gynecological condition known as \nendometriosis [1] and has endometrial-like tissue outside the \nuterus and is a primary cause of pelvic discomfort and infertility \n[2]. Up to 50% of women with infertility, 50–60% of women \nand teenage girls experiencing chronic pelvic pain [1], and \n6–10% of women of reproductive age develop endometriosis \n[3]. Peritoneal disease is a chronic, progressive illness that \ndependent on estrogen for growth, by which, endometriosis \ncauses intrinsic Estrogen Receptor (ER)-β pathway activation \nand enhanced local estradiol (E2) synthesis, which makes the \nER pathway extremely active. A recent paper outlines several \nmechanisms that could lead to this [4]. Endometriosis is caused \nby retrograde menstruation of steroid hormone-sensitive \nendometrial cells and tissues; these cells implant on peritoneal \nsurfaces and cause inflammation. This response is accompanied \nby angiogenesis, adhesions, fibrosis, scarring, neuronal \ninfiltration, and anatomical distortion [2].\nAlthough endometriosis has been extensively studied for many \nyears, little is known about its etiology, and its pathophysiology \nis not yet fully understood [5]. However, the retrograde \nHistopathological investigation  of the effects of Trastuzumab on the uterus in a rat \nmodel with endometriosis\nOmur Gulsum Deniz1, \n Pinar Kirici2, \n Ebru Annac3, \n Selcuk Kaplan4\n1Bolu Abant İzzet Baysal University, Faculty of Medicine, Department of Histology and Embryology, Bolu, Türkiye\n2Malatya Turgut Ozal University, Faculty of Medicine, Department of Obstetrics and Gynecology, Malatya, Türkiye\n3Adiyaman University, Faculty of Medicine, Department of Histology and Embryology, Adiyaman, Türkiye\n4Adiyaman University, Faculty of Medicine, Department of Obstetrics and Gynecology, Adiyaman, Türkiye\nReceived 28 July 2025; Accepted 08 September 2025\nAvailable online 27 October 2025 with doi: 10.5455/medscience.2025.07.206\nContent of this journal is licensed under a Creative Commons Attribution-NonCommercial-NonDerivatives 4.0 International License. \nAbstract\nIt was aimed to investigate histopathological effects of trastuzumab on the uterus in a rat model with experimentally induced endometriotic tissue in the present \nstudy. In this study, 28 female Wistar albino rats (10-12 weeks old, 250-280 g) were divided into 4 groups (n =7). After a 7-day acclimation period, rats in the \nestrous phase were selected. The control group received no endometriosis induction; fat tissue was attached to the peritoneum and the abdomen was sutured.  \nThe endometriosis group underwent surgical induction of endometriosis using an auto-transplantation method, where uterine horn fragments were sutured \nto the peritoneum and mesentery. After a 4-week recovery period, the lesion size was measured, but no treatment was given. The endometriosis+Trastuzumab \ngroup received the same induction procedure as the endometriosis group, followed by intraperitoneal administration of trastuzumab (5 mg/kg) for 4 weeks. \nThe trastuzumab group had no endometriosis induction but received the same trastuzumab dosage and schedule. Every animal tissue sample was obtained, and \nhistopathological analysis was performed. In histopathological analysis, there was a significant difference between the Endometriosis group which had the most \nsevere pathological changes compared to the control group (p<0.01). As well as; Endometriosis+Trastuzumab groups showed significant improvement in terms \nof epithelial integrity (p<0.05), Mast cell infiltration (p<0.01), glandular degeneration (p<0.05), and fibrosis (p<0.05), compared with the endometriosis group. In \naddition, no statistically significant difference was detected in the control and trastuzumab groups (p>0.05). Trastuzumab treatment resulted in protective effects \non endometriosis-affected uterine tissue. In this context, histopathological results suggested that trastuzumab may be beneficial in treating damage caused by \nexperimentally induced endometriosis.\nKeywords: Endometriosis, trastuzumab, uterus, rat, histopathology\nCorresponding Author:  Omur Gulsum Deniz, Bolu Abant \nİzzet Baysal University, Faculty of Medicine, Department of \nHistology and Embryology, Bolu, Türkiye\nEmail: omur.denizomu@gmail.com\nCITATION\nDeniz OG, Kirici P, Annac E, Kaplan S. Histopathological \ninvestigation of the effects of Trastuzumab on the uterus in a rat \nmodel with endometriosis . Med Science. 2025;14(4):1047-53.\n\nDOI: 10.5455/medscience.2025.07.206Med Science 2025;14(4):1047-53\n1048\nmenstruation/transplantation theory proposed by Sampson [6] is \nthe most widely accepted explanation for the pathophysiology of \nendometriosis. This theory postulates that endometrial fragments \nadhere and bind to peritoneal surfaces. Sampson's theory states \nthat a cellular blood supply and endometrial neoangiogenesis \nand proliferation are essential for the implantation of endometrial \ntissues onto peritoneal and subperitoneal surfaces [6]. \nNumerous malignancies in humans, such as breast, ovarian, \nand endometrial cancers, have been linked to human epidermal \ngrowth factor receptor 2 (HER2) gene amplification and \nHER2 protein overexpression which, upon ligand activation, \ncan dimerize and trigger signal transduction via the PI3K and \nmitogen-activated protein kinase signaling pathways [7]. In \nthis context, anti-HER2 treatments are now a standard of care \nfor certain of these malignancies [7]. By binding to HER2, \ntrastuzumab inhibits the growth, multiplication, and survival of \ncancer cells both directly and indirectly [8]. \nCurrent treatment limitations for endometriosis, while surgical \ndiagnosis affords the possibility for concurrent therapy, \nand the removal of severe endometriosis demands specific \nsurgical expertise. An incorrect surgical technique may result \nin inadequate treatment, which can lead to disease recurrence \nand pain, central sensitization, surgical complications, and \ndiminished fertility [9]. In addition to that hormonal treatments \nthat diminish endogenous estradiol levels are not an option for \nlong-term treatment because of undesirable adverse effects, \nincluding irreversible bone mineral density (BMD), which leads \nto osteoporosis. [10]. Medication development is difficult when \nmultiple requirements for the perfect endometriosis medicine \nare considered, including the simultaneous treatment of pain and \ninfertility, an acceptable safety profile, safe long-term usage, and \na no contraceptive impact for women of childbearing age. As a \nresult, there is a clear need for new treatment options that target \nthe underlying pathology of endometriosis more effectively \nand with fewer side effects than current hormonal or surgical \ntreatments. \nTrastuzumab is an antineoplastic biologic agent approved by \nthe Food and Drug Administration (FDA) in the United States \nfor medical use in the treatment of HER2-positive breast and \ngastric cancers in 1998, it became one of the earliest available \n\"targeted\" chemotherapies [11]. It is on the World Health \nOrganization's List of Essential Medicines [12]. Trastuzumab \nmay be a useful part of targeted therapy because HER2 protein \noverexpression or gene erbB2 amplification is seen in 25% to \n30% of serous endometrial carcinomas [11]. Trastuzumab may \nprovide a potential treatment path worth exploring. So, we aimed \nto investigate histopathological effects of trastuzumab on the \nuterus in a rat model with experimentally induced endometriotic \ntissue. \nMaterial and Methods\nAnimals and Experimental Protocol\nUterus tissues of the animals were used in the present study after \nwas approved by the Adıyaman University Animal Experiments \nLocal Ethics Committee (no: 2022/029 dated 26/05/2022). \nIn this research, 28 female Wistar albino rats, each weighing \nbetween 250 and 280 grams and aged 10 to 12 weeks, were \ndivided into four groups, with each group containing seven \nanimals. For seven days, no interventions were made to allow \nthe caged animals for adaptation. After verifying the animals' \nreproductive cycles with vaginal swabs, rats in the oestrous \nphase were randomly selected. The following rat groups were \nused in the experiment: \nGroup 1 (Control group) (n = 7)  After locating the right and \nleft uterus horns, the abdominal wall was closed using 4-0 nylon \nsutures, and fat tissues were adhered to the ventral abdominal \nwall peritoneum without utilizing endometriotic implants [13]. \nGroup 2 (Endometriosis group) (n = 7)  In this study, \nendometriosis was induced using an auto-transplantation \napproach. Rats were given 50 mg/kg ketamine and 10 mg/kg \nxylazine intraperitoneally. After an abdominal incision, the right \nand left uterus horns were detached and cut into three to five (3-5 \nmm) equal portions. The small bowel mesentery and peritoneum \nwere then inoculated with endometriotic tissue [14]. After \nsurgically induced endometriosis, all rats were given 4 weeks \nto recover. After four weeks, rats underwent surgery to study \nthe development of endometriotic implants. The endometriotic \nvolume and implant surface areas were determined using the \nformula π/6 𝗑 length 𝗑 width 𝗑 height. The peritoneal cavity \nwas closed, the endometriotic lesions were photographed, the \nlesion diameters were measured, and no further treatment was \nadministered for four weeks [13]. \nGroup 3 (Endometriosis+Trastuzumab group) (n = 7) Similar \nto Group 2, endometriotic foci have been generated. Following \nthe measurement of the endometriotic volume and the taking \nof pictures of the lesions, 5 mg/kg trastuzumab [13] was given \nintraperitoneally for 4 weeks. \nGroup 4 (Trastuzumab group) (n = 7)  The abdominal wall \nwas closed with 4-0 nylon stitches after the adnexa and uterus \nhorns were identified. Trastuzumab (5 mg/kg) was injected \nintraperitoneally for 4 weeks, beginning simultaneously with \nGroup 3.\nHistopathological Evaluation\nWhen the experimental application procedures were completed, \nuterus tissue samples belonging to the groups were taken and \ndetermined in 10% neutral-buffered formalin for 2 weeks. \nAfter the fixation process of the tissues was completed, routine \nhistological tissue follow-up consisting of alcohol, xylene and \nparaplast chemicals was performed. Tissue samples were then \nturned into paraffin blocks. Thin sections with a thickness of \n5 μm were taken from paraffin blocks for histopathological \nexamination. The prepared sections were deparaffinized using \nxylene and stained with Hematoxylin-eosin, Masson’s trichrome \nstaining and Toluidine blue staining method. The stained \nsections were examined with a Carl Zeiss brand Axiocam ERc5 \nmodel digital camera attachment microscope and evaluated \nsemi-quantitatively between 0 and 3. If no change occurred, the \n\nDOI: 10.5455/medscience.2025.07.206Med Science 2025;14(4):1047-53\n1049\nscore was 0; if mild damage was present, the score was 1; if \nmoderate damage was evident, the score was 2; and if severe \ndamage was observed, the score was 3.\nStatistical Analysis\nSPSS version 21.0 analysis program was used in the statistical \nanalysis of the numerical data of the groups obtained from our \nstudy. The conformity of the data to the normal distribution \nassumption was evaluated by the Shapiro-Wilk test. In the \ncomparison of the continuous variables specified by the \nmeasurement, the data that fit the normal distribution were \nevaluated using One-Way ANOV A and the Bonferroni test \nas post-hoc. In the statistical evaluations, the difference was \naccepted to be statistically significant when p<0.05.\nResults\nHistopathological Findings of Uterus Tissue\nThe three layers of uterus tissue, endometrium, myometrium and \nperimetrium, were examined. Epithelial, glandular structures and \nconnective tissue areas were examined in detail. It was observed \nthat healthy tissue appearance was dominant in the control and \nTrastuzumab groups. It was determined that the single-layered \nprismatic epithelium of the endometrium and the loose connective \ntissue underneath were normal. Centrally located, round and oval \nnuclei were observed in these epithelial cells lining the lumen. \nThe stromal cells in the connective tissue beneath the epithelial \nlayer were located among the collagen fibers that showed a \nregular course (Figures 1A and B and Figures 3A and B). The \nblood vessels in the connective tissue appeared to maintain their \nstructural integrity. Additionally, it was determined that the \nuterus gland lumens in the endometrium were clearly visible and \nthe cells forming the gland epithelium were in a single-layered \ncuboidal epithelial structure (Figure 2A and B). Mast cell density \nin the connective tissue was found to be normal (Figure 4A and \nB). There were no signs of edema, fibrosis, hemorrhagic areas, \nor inflammation in any area in the tissue samples examined in \nthe control and Trastuzumab groups. In the endometriosis group, \ndegeneration and vacuolization findings were observed in the \nepithelium of the endometrium layer (Figure 1C). Fibrosis was \nobserved in the connective tissue beneath the epithelium (Figure \n3C). At the same time, degeneration and vacuolization were \nnoticed in the cuboidal epithelial cells that form the structure of \nthe endometrial glands. There was also evidence of inflammation \n(Figure 2C). An increase in Mast cell density in connective \ntissue was observed (Figure 4C). No hemorrhagic areas were \nfound in the tissue samples examined. In the Endometriosis+ \nTrastuzumab group, it was observed that the degenerative effects \non the endometrium layer were improved. It was noticed that the \nstructure of the single-layered prismatic epithelium surrounding \nits lumen was preserved (Figure 1D). A small amount of fibrosis \nwas observed in the connective tissue under the epithelium \n(Figure 3D). In addition, it was determined that most of the \nglands in the relevant connective tissue maintained their healthy \nstructure. In addition, there was the presence of degenerated \nglands. No degeneration was observed in the cubic epithelial \ncells that make up its structure (Figure 2D). A decrease in mast \ncell density in the connective tissue was detected compared to \nthe endometriosis group (Figure 4D). No hemorrhagic areas or \nany signs of inflammation were observed in the tissue samples \nexamined. \nIn light of this information, a statistically significant difference \n(p<0.01) was found between the control and endometriosis \ngroups in terms of glandular degeneration (Figure 5A), epithelial \ndegeneration (Figure 5B), fibrosis (Figure 5C), and Mast cell \ndensity (Figure 5D). In addition, trastuzumab was shown to \nsignificantly minimize the effects of glandular degeneration, \nepithelial degeneration, and fibrosis at p<0.05, and Mast cell \ndensity at p<0.01 level.\nFigure 1.  A, B, C, and D, histological images (Hematoxylin-eosin Staining) \nof the Control, Trastuzumab, Endometriosis, and Endometriosis+Trastuzumab \ngroups at x40 objective magnification, respectively. Black arrow, prismatic \nepithelium with normal structure; Black arrowhead, degenerated epithelium; \nasterisk, inflammation.\nFigure 2.  A, B, C, and D, Histological images (Hematoxylin-eosin Staining) \nof the Control, Trastuzumab, Endometriosis and Endometriosis+Trastuzumab \ngroups at x40 objective magnification, respectively. Black arrow, gland with \nnormal structure; Black arrowhead, degenerated gland; asterisk, inflammation.\n\nDOI: 10.5455/medscience.2025.07.206Med Science 2025;14(4):1047-53\n1050\nFigure 3. A, B, C, and D, Histological images (Masson’s trichrome staining) \nof the Control, Trastuzumab, Endometriosis and Endometriosis+Trastuzumab \ngroups at x40 objective magnification, respectively. Asterisk, fibrosis.\nFigure 4. A, B, C, and D, Histological images (Toluidine Blue staining) of the \nControl, Trastuzumab, Endometriosis and Endometriosis+Trastuzumab groups \nat x40 objective magnification, respectively. Black arrow, Mast cell.\nFigure 5. Glandular degeneration (A), epithelial degeneration (B), fibrosis (C) and Mast cell density (D) parameters in the \nuterus tissue from all groups (n=7). Differences at the p<0.05 level are indicated by “*” and those at the p<0.01 level by \n“**”\n\nDOI: 10.5455/medscience.2025.07.206Med Science 2025;14(4):1047-53\n1051\nDiscussion\nEven though the first written descriptions of endometriosis \nwere published more than a century ago, it has proven difficult \nto comprehend the disease's etiology and natural history [15]. \nThere were numerous classic literatures from antiquity to the \n19th century that described symptoms that were thought to be \nproof that endometriosis existed [16]. Nonetheless, the frequent \nuse of rat and other models of experimental endometriosis \nhas made it possible to identify several potentially targetable \nmechanisms that would otherwise contribute to the development \nof this illness [15]. Endometriosis is believed to be caused \nby an intricate combination of immunological response, \nneuro angiogenesis, and oxidative balance [17,18]. In a study \nconducted a thorough pathological examination of the rat \nendometriosis model. It demonstrated the presence of immune \ncells such as mast cells, eosinophils, plasma cells, lymphocytes, \nand macrophages in the peritoneal stroma surrounding \nimplanted uterus tissue. The results indicate that the rat model \nclosely resembles human endometriosis, making it appropriate \nfor histopathological research [19]. \nTrastuzumab's histopathological effects on the uterus were \nexamined in this work using a rat model of experimentally \ninduced endometriotic tissue. There was significant difference \nbetween (endometriosis group) and (control and Trastuzumab \ngroups) in terms of epithelium of the endometrium layer, that in \n(control and Trastuzumab groups) the single-layered prismatic \nepithelium of the endometrium and the loose connective \ntissue underneath were normal while in endometriosis group \nshows degeneration and vacuolization in it. Besides, in the \npresent study, a significant difference was found between the \nendometriosis group and the Endometriosis+Trastuzumab \ngroup, demonstrating significant improvements in degenerative \neffects on the endometrial layer and a reduction in inflammation. \nAn investigation that induced an endometriosis model in rats to \nstudy the efficacy of natural and synthetic medications in treating \nendometriosis, found in the expression of the angiogenic marker \nvascular endothelial growth factor (VEGF), pro-inflammatory \nCyclooxygenase (COX)-2 and Interleukin (IL)-6 protein \nmarkers, and anti-apoptotic Bcl-2 was significantly elevated in \nthe endometriosis group [20] which came in support of what \nwe obtained in our study, significant pathological alterations \nwere consistently seen in the endometriosis group including \ndegeneration and vacuolization, inflammation, epithelial \ndamage, and Mast cell density.\nThe first anti-HER2 drug created, trastuzumab, is a humanized \nmonoclonal antibody that attaches to the extracellular [21], \nligand-binding domain [8], juxta membrane region of the HER2 \nreceptor and inhibits HER2 signaling activity, which leads to \ncell cycle arrest, a decrease in angiogenesis, and an inhibition \nof downstream signaling pathways [8]. In our study, a decrease \nin histological evidence of damage in endometriotic areas in \nthe transtuzumab-treated group was associated with the drug's \nantiproliferative effect. Based on these data, it is conceivable to \nsupport the concept that endometriotic regions include HER2 \nreceptors. Trastuzumab also reduced epithelial damage in our \nexperiment, consistent with findings from another study where \nit showed improved cellular cytotoxicity over time compared to \nT-DM1 [22].\nAccording to a review, fibrosis is a result of several cell types in \nall endometriosis symptoms. Inducing the release of substances \nthat permit endometriosis deposit and fibrosis, fibrogenesis \nis facilitated by activated platelets, macrophages, ectopic \nendometrial cells, and sensory nerve fibers [23]. In this context, \nthere was significant difference in our investigation between \nendometriosis and Endometriosis+Trastuzumab groups in terms \nof fibrosis. The present study demonstrated that trastuzumab \ntreatment reduced fibrotic tissue formation in endometriosis \nfoci. This effect may be explained by inhibition of HER2-\nmediated fibrogenesis signaling pathways and suppression of \nstromal cell activity.\nEndometriosis is a chronic inflammatory illness related to \nestrogen. E2, a physiologically active estrogen, exacerbates the \npathogenic processes such as inflammation and growth, as well \nas the pain symptoms associated with endometriosis [24]. Mast \ncells produce proteases such tryptase, which destroy extracellular \nmatrix components and impair epithelial integrity. This action \nadds to the epithelial damage found in endometriotic lesions. \nThe role of estrogen in Mast cell activity has been acknowledged \nas a possible contributor to the pathophysiology of various \nallergic and chronic inflammatory disorders. Nevertheless, \ndetailed knowledge regarding the interaction between \nendocrine and immune elements in endometriotic lesions is \ninsufficient, leaving unclear whether this interaction plays a role \nin the participation of Mast cells in disease pathophysiology \n[25]. In our study there was a significant difference between \nEndometriosis and Endometriosis+Trastuzumab groups in terms \nof Mast cell density.  In this context, findings in the treatment \ngroup indicate a decrease in mast cell density, suggesting that \ntrastuzumab may have therapeutic efficacy in reducing the \npathological effects of endometriosis. Endometrial glands are \ntubular structures, lined with a simple columnar epithelium, \nlocated in the functional layer of the endometrium that coats \nthe uterus [26]. The histological diagnosis of endometriosis \nmay be complicated or obscured by an atypical appearance of \nthe endometrial glands or the stroma, which can be influenced \nby inflammation, edema, or hemorrhage [27]. In our study we \nfound a significant difference in cuboidal epithelial cells that \nform the structure of the endometrial glands degeneration and \nvacuolization were noticed in Endometriosis group while there \nwas no degeneration observed in the cubic epithelial cells in \nEndometriosis+Trastuzumab group.\nThe use of a rat model limits the scope of this investigation, \nand the effectiveness of trastuzumab still requires confirmation \nthrough clinical research in humans. Although Trastuzumab's \nside effects most be considered which include weariness, muscle/\n\nDOI: 10.5455/medscience.2025.07.206Med Science 2025;14(4):1047-53\n1052\njoint pains, discomfort, palpitations, cough and chills, and \nlung infiltration [28]. However, these side effects are typically \nmoderate and do not limit its use. In addition, cardiotoxicity and \ninterstitial pneumonia are major complications that may cause \nthe cessation or discontinuation of treatment [29]. Furthermore, \nlet's not underestimate that clinical studies reveal that two-thirds \nof patients do not respond to trastuzumab, and people who \noriginally responded later acquire resistance to this medication \n[30]. On the other hand, its substantial anti-inflammatory and \nantiproliferative properties point to possible treatment benefits \nfor endometriosis [13]. More research is required to better \nunderstand its mechanism and safety profile.\nConclusion\nThis study discovered that trastuzumab treatment resulted in \nsignificant histological improvements in endometrial structure \nin rats with induced endometriosis, including decreased \ndegeneration, inflammation, and Mast cell activity. The history \nof endometriosis has garnered more attention throughout the last \n20 years [16] use of rodent models a far more comprehensive \nunderstanding of endometriosis, by revealing its cellular \npathology, early risk factors, and potential treatment targets. \nVernon and Wilson [31] was one of the earliest who described \nthe rat surgical model, despite the fact that all animal models \nhave limitations the rat surgery model had provide important \nunderstanding of endometriosis-related peritoneal environment, \ninflammatory processes, the early stages of disease progression, \nand the function of some treatment responses and in vivo \nendometriosis proven effective for evaluating the therapeutic \npotential of natural or synthetic treatments. The best chance \nto find treatment approaches to stop or reverse this mysterious \ncondition is through the ongoing development of animal models \nthat help to understand the mechanisms behind the development \nof endometriosis.\nThe relatively short duration of the investigation constituted a \nlimitation in terms of the long-term consequences of treatment \nand analysis. In this context, a longer investigation duration might \nbe beneficial for examining oxidative balance in conjunction \nwith the progression of chronic inflammation. Future research \nwith additional experimental subjects is needed to support the \ncombination and separate usage of trastuzumab in terms of long-\nterm outcomes and adverse effects of endometriosis.\nConflict of Interests\nThe authors declare that there is no conflict of interest in the study.\nFinancial Disclosure\nThe authors declare that they have received no financial support for the study. \nEthical Approval\nThe present study was approved by the Adıyaman University Animal Experiments \nLocal Ethics Committee (no: 2022/029 dated 26/05/2022). All experimental \nprocedures were carried out accordance with the U.K. Animals (Scientific \nProcedures) Act, 1986 and associated guidelines, EU Directive 2010/63/EU for \nanimal experiments, or the National Institutes of Health guide for the care and \nuse of Laboratory animals (NIH Publications No. 8023, revised 1978).\nReferences\n1. Butler D, Wang H, Zhang Y , et al. 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Vernon MW, Wilson EA. Studies on the surgical induction of endometriosis \nin the rat. Fertil Steril. 1985;44:684-94.","source_license":"CC0","license_restricted":false}