{"paper_id":"b65c1e73-2913-4d3d-bfa3-fe77de2201da","body_text":"Paul et al. Middle East Fertility Society Journal            (2025) 30:6  \nhttps://doi.org/10.1186/s43043-025-00219-8\nREVIEW Open Access\n© The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which \npermits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the \noriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or \nother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line \nto the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory \nregulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this \nlicence, visit http://creativecommons.org/licenses/by/4.0/.\nMiddle East Fertility\nSociety Journal\nAn overview of endometriosis and molecular \ntarget-based therapeutic approach\nDeepraj Paul1*  , Rohini Agrawal1 and Mohammed Asif Iqbal2 \nAbstract \nBackground Endometriosis has become a global concern. Fifty percent of the affected women become infertile. Ten \npercent of the female population, which represents women in their reproductive age and girls, is affected globally. It \nshows a strong correlation with thyroid, endometrial, and breast cancer. It disrupts the psychological, social, and eco-\nnomic wellbeing and sexual life of women.\nMain body Modern hormonal therapy relies upon estrogen–progestin combinations. Other drugs include pro-\ngestins, gonadotropin-releasing hormone agonists and antagonists. Some patients remain non-responsive to these \ntherapies, and others show adverse effects such as intolerance, weight gain, acne, and seborrhea. Similarly, surgery \nhas its own complications which include late bowel, ureteral perforations, recto-vaginal, and uretero-vaginal fistulas. \nNeither modern therapeutic nor surgical approaches could alleviate endometriosis. Besides, the cost of treatment \nis overburdening. This necessitates the designing of an alternative therapeutic approach which could alleviate endo-\nmetriosis. This has led to the identification of molecular targets and the exploration of different phytoconstituents \nthat could modulate these targets.\nConclusion Formulation containing different phytoconstituents such as apigenin, genistein, resveratrol, \n5α-hydroxycostic acid, hydroxyisocostic acid, anthocyanins, quercetin, naringenin, kaempferol, withaferin-A, ursolic \nacid, shogaol, curcumin, demethoxycurcumin, capsaicin, ellagic acid, 6‐paradol, 6‐gingerol, carnosic acid, tuberoste-\nmonine-O, rosmarinic acid, luteolin, granatin-B, and licochalcone-A may be useful in the treatment of emdometriosis. \nThis formulation may decrease the proliferation of ectopic endometrial stromal cells, their invasion, vascularization, \npain sensation, inflammation, gestational diabetes mellitus, and fetal growth restriction. There may be an increase \nin the fertility rate also. This is due to its ability to regulate the expression of many molecular targets such as VEGF-\nA/VEGFR2 pathway, p38MAPK/ERK-1/2/PI3K/protein kinase B (AKT), HIF-1α, IL-1β, IL-2, IL-6, IL-8, IL-10, IL-17A, IL-18, \nIL-33, TNF-α, NF-kB, IFN-γ, IGF-1-induced activation of IGF-1R, ER-α, and ER-β receptors, miR-95, miR-103, miRNA-138, \nmiRNA-155, miR-183, miR-223, MMP-1, MMP-2, MMP-3, MMP-9, lncRNA-MEG3, lncRNA-H19, Ang-1 mRNA, Ang-2 \nmRNA, mRNA of urokinase plasminogen activator, mRNA expression and secretion of leptin, CD31, Tie-2, MCP-1 \nmRNA and protein, HGF, Nrf2, HO1, Keap1, COX-2, PGE-2, MKNK1, and human DNA TOP3A. However, further research \nis required to determine the safety, compatibility, and therapeutic efficacy of this formulation.\nKeywords Endometriosis, Estrogen, Progesterone, Inflammation, Pathogenesis, Plant products\nBackground\nEndometriosis is a chronic inflammatory disorder of the \nuterus triggered by excessive production of estrogen by \nthe ovaries [1, 2]. Patients experience severe chronic pel -\nvic pain due to the growth of endometrial tissue outside \nthe uterus [3, 4]. Other types of pain include dysmenor -\nrhea, dyspareunia, dyschezia, and dysuria [5]. The biggest \n*Correspondence:\nDeepraj Paul\ndeeprajcology81@gmail.com\n1 Department of Pharmacology, College of Pharmacy, JSS University, Uttar \nPradesh, Noida 201301, India\n2 Department of Pharmaceutical Chemistry, Yenepoya Pharmacy \nCollege and Research Centre, Yenepoya (Deemed to Be University), \nMangalore 75018, India\n\nPage 2 of 27Paul et al. Middle East Fertility Society Journal            (2025) 30:6 \nconcern with endometriosis is that 50% of the affected \npopulation becomes infertile. It is estimated that 10% \nof the female population, representing women in their \nreproductive age and girls, is affected globally [6]. The \ngraveness of the disorder can be measured by its strong \ncorrelation with thyroid, endometrial, and breast can -\ncer [7, 8]. It disrupts the psychological, social, and eco -\nnomic wellbeing and sexual life of women [5]. Anxiety \nand depression are the most common observations in \nendometriosis [4]. To date, there is no cure available for \nendometriosis [9]. Pharmacological intervention for \nsymptomatic endometriosis through hormonal therapy \ndepends on estrogen-progestin combinations. Other \ndrugs include progestins, gonadotropin-releasing hor -\nmone agonists and antagonists. Some patients remain \nnon-responsive to these therapies and others show \nadverse effects such as intolerance, weight gain, acne, \nand seborrhea [10]. Similarly, surgical intervention has \nits own complications which include late bowel, ureteral \nperforations, recto-vaginal, and uretero-vaginal fistulas \n[11]. The recurrence rate of endometriosis after 2  years \nof conservative surgery was found in the range of 9.2–\n29.4%, whereas the recurrence rate after a follow-up for \n12 years was found to be 56.4% [12]. Neither therapeutic \nnor surgical approach could alleviate the disorder; even \npostoperative medical treatment could not prove its ben -\nefit [13]. Besides, the cost of treatment is overburdening \n[14]. Most importantly, medical treatment after surgi -\ncal intervention can only delay the recurrence of endo -\nmetriosis but cannot completely cure the disorder [15]. \nHence, it is crucial to understand the risk factors, com -\nplications, pathological correlations, and pathogenesis of \nendometriosis for a better therapeutic approach. Inter -\nestingly, many plant extracts have been found to sup -\npress the pathological parameters of endometriosis [16]. \nThis makes it inevitable to revisit the disorder to identify \npotential therapeutic targets and explore the potential \nof purified phytoconstituents to modulate these targets. \nThis review will try to propose a formulation containing a \nmixture of different phytoconstituents. This formulation \nis expected to alleviate endometriosis and improve the \nchances of pregnancy.\nMain text\nRisk factors\nLadies presenting menstrual cycles with a greater num -\nber of bleeding days are at higher risk of endometriosis \n[17]. First menstrual cycle occurring before the age of \n11, shorter menstrual cycle (less than 27  days), obe -\nsity, Caucasian race, age between 25 and 29, daily alco -\nhol consumption (10  g per day), red meat consumption \n(more than 2 servings per day), smoking, etc., are some \nof the risk factors for endometriosis [18]. Exposure to \ncertain chemicals such as polychlorinated biphenyls [19], \narsenic, cadmium, lead, and mercury [20] can induce \nendometriosis. First-degree relatives are at higher risk \nof developing endometriosis [17]. Women in Rh-nega -\ntive blood group show two times higher susceptibility to \ndevelop endometriosis compared to the control group \nbut the ABO system of blood grouping did not show any \nsignificant susceptibility compared to the control group. \nInvolvement of genetic components is suspected [21]. A \nrecent study has proved a strong genetic basis for endo -\nmetriosis. Forty-two genome-wide significant loci have \nbeen identified for endometriosis. Thirty-one of these \ngenes have been reported for the very first time [22]. \nCertain coagulation factor such as von Willebrand fac -\ntor (vWF) shows a positive causal association with endo -\nmetriosis of the pelvic peritoneum and ovary. This may \nbe related to a decreased plasma level of ADAMTS13 (A \ndisintegrin and metalloproteinase with thrombospon -\ndin motifs 13), which is required for cleaving vWF and \nmaintaining its plasma level [23]. Some enzymes may \nincrease the susceptibility to endometriosis. A slow acet -\nylation phenotype of the enzyme N-acetyltransferase 2 is \nassociated with a 130% increased risk of endometriosis \n[24]. Similarly, catechol-O-methyltransferase (COMT) \n158G/A polymorphism may increase the susceptibility \nto endometriosis and adenomyosis [25]. Respiratory ail -\nments can increase the susceptibility to endometriosis \nin a particular age group. Chronic obstructive pulmo -\nnary disease (COPD) in 40–60 years of women increases \nthe susceptibility to endometriosis compared to women \nwithout COPD [26]. Hypovitaminosis D has been identi -\nfied as a potential risk factor for endometriosis [27].\nComplications\nEndometriosis increases the chance for irritable bowel \nsyndrome by more than two folds compared to women \nwithout endometriosis [28].\nEndometriosis accompanied by adenomyosis is \nresponsible for a significantly lower live birth rate than \nendometriosis alone [29]. First-time mothers with endo -\nmetriosis generally represent abnormally located pla -\ncenta, are more prone to have a premature baby, and \nundergo cesarean delivery [30, 31]. Endometriosis signifi-\ncantly increases the risk of gestational diabetes in natu -\nral pregnancies but has no effect on conception through \nassisted reproductive technologies [32]. Endometriosis \nincreases the chance of preeclampsia in women who con-\nceive spontaneously [33].\nEndometriosis significantly increases the risk of \nischemic heart disease and cerebrovascular disease [34]. \nCerebrovascular disease is again a risk factor for Alzhei -\nmer’s disease (AD). People with cerebrovascular disease \nshow a significant increase in “formin-like protein 2, ” \n\nPage 3 of 27\nPaul et al. Middle East Fertility Society Journal            (2025) 30:6 \n \nwhich is responsible for amyloid and phosphorylated tau \ndeposition and progression of AD [35].\nEndometriosis favors a higher rate of high-risk human \npapillomavirus (HPV) infection [36]. A subsequent study \nhas confirmed the presence of high-risk HPV infection \nin 60% of endometriosis patients. High-risk HPV infec -\ntion in the upper genital tract is associated with infertil -\nity [37]. A newer study has also correlated HPV infection \nwith pain and infertility in endometriosis patients [38]. \nThe concern arises from the fact that the presence of \nhigh-risk HPV (predominantly type 16 and 18 HPV) \nshows the most frequent association with cervical cancer \n[39].\nPathological correlation\nWomen with both anterior and posterior adenomyosis \nhad shown higher co-existence of ovarian endometriosis \nand pelvic adhesion, whereas women with only posterior \nadenomyosis had shown heavy menstrual bleeding and \noviduct obstruction. Women with anterior adenomyo -\nsis had shown a higher incidence of leiomyoma [40]. All \nthese pathologies and endometriosis are interlinked. The \nprevalence of adenomyosis in endometriosis was 91.1%, \nwhereas the prevalence of endometriosis in adenomyo -\nsis was 80.6% [41]. Similarly, endometriosis is described \nas the most common reason behind pelvic adhesion; \n37.6% of pelvic adhesions result from endometriosis [42]. \nStudies have shown that other than endometrium, tubal \nmucosa also plays a role in endometriosis; endometriotic \nlesions so produced can in turn lead to tubal dysfunction \n[43].\nIn reality, endometrial tissue can be implanted any -\nwhere, but the preferred places are the ovary and pel -\nvic peritoneum [44]. A study has proved the correlation \nbetween adenomyosis and deep endometriosis, specifi -\ncally rectosigmoid endometriosis [45]; it is noteworthy \nthat deep endometriosis can infiltrate into uterosacral \nligaments, rectovaginal space, gastrointestinal tract, uri -\nnary tract, and rectosigmoid region. Involvement of the \nrectosigmoid region was observed in almost 90% of the \ncases with endometriosis [46]. Endometriosis can cause \ncomplete rectosigmoid obstruction [44]. Similarly, \nanother study has shown the correlation between leio -\nmyoma, adenomyosis, and endometriosis. One hundred \neighty-one out of 208 leiomyoma patients had endome -\ntriosis, and 9 out of the remaining 27 had adenomyosis \nas well as leiomyoma. Only 18 patients were affected with \nleiomyoma alone [47].\nEndometriosis and eleven pain-conditions have \nshown a significant genetic correlation. Such pains also \ninclude migraine, back pain, and multisite chronic pain. \nCertain inflammatory conditions such as asthma and \nosteoarthritis show a significant genetic correlation with \nendometriosis [22].\nClassification/grading/scoring of endometriosis\nUltrasound-based endometriosis staging system and \ntransvaginal ultrasound have classified the disorder into \nthree stages. Stage I represents normal mobility of the \novaries, absence of non-bowel and bowel deep infiltrating \nendometriosis, normal “Pouch of Douglas”(POD), and \nthe presence or absence of site-specific tenderness. This \nstage is identified as “mild stage disease” by the surgical \ncomplexity-based grading system, also categorized as \nlevel 1. Stage II represents endometrioma, with or with -\nout immobile ovaries, with or without non-bowel deep \ninfiltrating endometriosis. However, POD remains nor -\nmal. This is identified as “moderate stage disease” by the \nsurgical complexity-based grading system, also catego -\nrized as level 2. Stage III represents bowel deep infiltrat -\ning endometriosis, the presence or absence of immobile \nendometrioma, and the presence or absence of POD. \nThis is identified as a “higher stage disease” by the surgi -\ncal complexity-based grading system, also categorized as \nlevel 3 [48].\nThe revised American Society for Reproductive Medi -\ncine (rASRM) considers endometriosis of the peritoneum \nand ovary, obliteration of POD, and adhesions of the \novary and fallopian tube for the purpose of grading endo-\nmetriosis. rASRM classifies endometriosis into 4 stages. \nStage 1 is graded as “minimal” and has a score range of \n1 to 5; stage 2 is graded as “mild” and has a score range \nof 6–15; stage 3 is graded as “moderate” and has a score \nrange of 16–40; stage 4 is graded as “severe” and assigned \na score more than 40. The points are allotted based on \nthe size of the lesions and the nature of the lesions such \nas superficial or deep. In case of endometriosis of ova -\nries, if a lesion on the ovary is less than 1 cm in size and \nsuperficial in nature, then the score allotted is 1. If the \nsize of the superficial lesion is between 1 and 3 cm, then \nthe score allotted is 2. If the size of the superficial lesion \nis more than 3 cm, then the score allotted is 4. In case of \na deep endometriosis if the size is less than 1  cm, then \nthe score allotted is 4. If the size is between 1 and 3 cm, \nthen the score allotted is 16. If the size is more than 3 cm, \nthen the score allotted is 20. Similarly, if obliteration of \nthe POD (also known as posterior cul-de-sac) alone is \nconsidered and if it is found to be partial then a score of 4 \nis assigned, which falls under stage 1. Complete oblitera -\ntion receives a score card of 40, which represents stage 3 \nendometriosis. Similarly, scores are allotted for adhesions \nobserved on the ovary and other places to indicate the \nstage of endometriosis. During the scoring of endometri -\nosis associated with the fallopian tube, higher scores are \nassigned if the end of the tube is found completely closed \n\nPage 4 of 27Paul et al. Middle East Fertility Society Journal            (2025) 30:6 \n[49–52]. This kind of scoring system helps to decide the \nfuture course of therapy.\nDespite its wide acceptance, the rASRM system faces \ncriticism for its failure to completely describe deep endo -\nmetriosis. Later, the Enzian classification came into the \npicture which relies upon three compartments (com -\npartments A, B, and C) to grade endometriosis. Com -\npartment A considers the vagina and rectovaginal space; \nscores are allotted based on the size of the lesions. If the \nsize of the lesion is less than 1 cm, then it receives a score \nof A1. If the size of the lesion is between 1 and 3 cm, then \nit receives a score of A2. If the size of the lesion is more \nthan 3 cm, then it receives a score of A3. Compartment \nB considers lesions on the uterosacral ligament (USL), \ncardinal ligaments, and pelvic sidewall. Here, different \ngrades such as B1, B2, and B3 are assigned based on the \nsize of the lesions. The measurement considered for grad-\ning the lesions remains the same as it was for compart -\nment A; however, different alphabets are used for grading \npurposes. Compartment C considers rectal aspects—any \nlesion on the anterior wall of the rectum which is located \nup to 16 cm from the anal verge. Endometriosis involv -\ning other organs of the pelvic cavity and distant organs \nis marked as “FA” indicating adenomyosis, “FB” indicat -\ning involvement of the bladder, “FU” indicating intrinsic \nureter involvement, “FO” indicating involvement of other \nlocations, and “FI” as intestinal involvement. Any lesion \nlocated above 16  cm from the anal verge is classified \nunder FI, and the grading size range remains the same as \nit was for A1 and B1. The grades assigned here are C1, \nC2, and C3. Other than this, many features are consid -\nered under this grading system. Irrespective of several \nfeatures, this system was criticized for not considering \nperitoneal or ovarian disease or adhesions. This led to the \nevolution of another system of classification called map -\nping [18, 50, 52–54].\nMapping focuses on the distribution pattern of the \nendometriosis lesions; for this purpose, peritoneal com -\npartments are divided into 5 zones. Zone 1 represents \nthe anterior compartment along with the anterior uterine \nserosa, round ligament, vesicouterine fold, and bladder. \nZone 2 represents the lateral compartment along with \nthe left and right ovary, ovarian fossa, tubes, mesosal -\npinx, uterosacral ligaments, parametrium, and the ure -\nter. Zone 3 represents the posterior compartment along \nwith the posterior uterine serosa, the pouch of Douglas, \nthe posterior vaginal fornix, and the bowel. Zone 4 rep -\nresents the abdominal wall. Zone 5 represents the dia -\nphragm. In case of unilateral endometrioma, zone 2 is the \nmost affected part followed by zones 3, 1, 4, and 5 [55]. \nUltrasound-guided mapping study is claimed to be very \neffective for preoperative planning and intraoperative \nmanagement of deep infiltrating endometriosis [56].\nAnother type of classification system is known as the \n“endometriosis fertility index” (EFI). This is considered to \nbe the first classification to predict the chances of fertil -\nity in patients who have undergone surgical diagnosis and \ntreatment of endometriosis [57]. This system considers \nstructures like the fallopian tube, fimbria, and ovary and \ntries to identify associated injuries, abnormalities, and \ndysfunction. The fallopian tube will be considered under \nthe “mild dysfunction” category if slight injury is present \nto the serosa of the tube. The term “moderate dysfunc -\ntion” is applicable if moderate limitation in mobility is \nobserved, and the tube presents moderate injury to the \nserosa or muscularis. The term “severe dysfunction” is \napplicable when mobility is severely impaired and the \npresence of fibrosis of the tube or mild to moderate sal -\npingitis isthmica nodosa is there. The term “non-func -\ntional” is used if complete obstruction of the tube and \nsevere fibrosis/salpingitis isthmica nodosa are observed. \nWhile considering the fimbria, the term “mild dysfunc -\ntion” is used to indicate slight injury with minimal scar -\nring. “Moderate dysfunction” represents moderate injury, \nscarring, and loss of fimbrial architecture and also rep -\nresents minimal intrafimbrial fibrosis. “Severe dysfunc -\ntion” indicates severe injury, scarring, and loss of fimbrial \narchitecture but moderate intrafimbrial fibrosis. “Non-\nfunctional” fimbria indicates severe injury with exten -\nsive scarring and complete loss of fimbrial architecture. \nThis stage also represents complete occlusion of the tube. \nWhile considering the ovary, the term “mild dysfunction” \nindicates the size of the ovary which is normal/nearly \nnormal and mild injury to the ovarian serosa. “Moder -\nate dysfunction” indicates moderate injury on the ovar -\nian surface. The size of the ovary reduces to one-third or \neven more. “Severe dysfunction” indicates severe injury \non the surface of the ovary. The size of the ovary reduces \nto two-third or even more. The term “non-functional” is \napplicable if the ovary is not present or encased in adhe -\nsions [58]. Scores are assigned based on the observation. \nThese scores help to decide the course of treatment. If \nthe EFI score is less than or equal to 4, then the recom -\nmendation is made for assisted reproductive technol -\nogy (ART). If the EFI score is between 5 and 6, then it is \nrecommended to go for non-ART management for 4 to \n6 months followed by ART. If the EFI score is more than \nor equal to 7, then it is recommended to go for non-ART \nmanagement for 6 to 9 months followed by ART [57].\nPathogenesis and therapeutic targets\nThe pathogenesis of endometriosis revolves around four \nfactors—genetic predisposition, progesterone resistance, \nestrogen dependence, and inflammation [59]. Among \nthese, progesterone resistance theory involving eutopic \nendometrium of women with and without endometriosis \n\nPage 5 of 27\nPaul et al. Middle East Fertility Society Journal            (2025) 30:6 \n \nfalls short of evidence and is somewhat ambiguous. Both \nnormal and eutopic endometrium have shown incon -\nsistent patterns of expression of progesterone recep -\ntors. Ectopic endometrium has shown a decrease in the \nexpression pattern of progesterone receptors [59, 60]. \nThe level of progesterone receptor B in eutopic endome -\ntrium was significantly lower in the endometriosis group \ncompared to normal women. The expression level of pro-\ngesterone receptor B in eutopic endometrium has shown \nan inverse correlation with the degree of endometriosis \n[61]. Suppressed progesterone receptor expression is the \nreason behind “chronic pelvic pain, infertility, inflamma -\ntory disorders, and cancer. ” Both progesterone receptors \nA and B are required to facilitate pregnancy in healthy \nfemales. In fact, an optimum ratio of these receptors is \nrequired to maintain pregnancy [62]. It is worth mention-\ning that progesterone receptor A has an inhibitory effect \non the expression of progesterone receptor B. This leads \nto the negative regulation of the effects of progesterone \nreceptor B and consequent hyperplasia of the endome -\ntrium and inflammation [62]. It is noteworthy that the \npredominance of progesterone receptor B is responsible \nfor progesterone signaling, whereas the predominance \nof progesterone receptor A decreases progesterone \nresponsiveness [63]. A disrupted progesterone response \nis a hallmark event in endometriosis [64]. This raises con-\ncern about the role and expression level of progesterone \nreceptor A in pregnancy among endometriosis patients \nbecause progesterone supports pregnancy. Normal preg -\nnancy shows a progressive increase in the levels of pro -\ngesterone from the first trimester to the third trimester. A \nlow progesterone level at 6 to 8 weeks indicates an abnor-\nmal intrauterine pregnancy or an ectopic pregnancy \n[65]. The chance of pregnancy in endometriosis patients \ncan be predicted from the finding that eutopic endome -\ntrium expresses a significantly higher level of progester -\none receptor A compared to normal women. Peritoneal \nendometriosis also shows the predominance of proges -\nterone receptor A. Interestingly, ovarian endometriosis \nalso shows a significantly higher expression of proges -\nterone receptor A compared to peritoneal endometriosis \n[66]. This indicates a negative role of progesterone recep-\ntor A in pregnancy among endometriosis patients. This \nalso implies the significance of progesterone resistance \nin endometriosis. A decreased expression and action of \nprogesterone receptors is associated with such resistance \n[62], and oxidative stress plays a great role in progester -\none resistance [67]. This is a real concern because oxida -\ntive stress and proinflammatory cytokines act in a cyclic \nmanner where one stimulates the production of the other \n[68]. In this way, the vicious cycle of progesterone resist -\nance and endometriosis will continue. Similar to proges -\nterone receptor A, the estrogen-alpha (ER-α) receptor \nhas a pathological association with peritoneal and ovar -\nian endometriosis [69]. It is also known to increase the \nchances of endometrial cancer, unlike the ER-β receptor, \nwhich has an opposing effect on ER-α function [69, 70]. \nER-α is correlated with the severity of pain and any fail -\nure to suppress ER-α expression by progestin therapy will \nlead to the recurrence of endometriosis after 1 year [71]. \nER-β will have an alleviating effect on endometriosis but \nexcess production of ER-β in stromal cells will have nega-\ntive effects. These include suppression of tumor necrosis \nfactor-alpha (TNF-α)-mediated apoptosis and induced \ninterleukin (IL)−1 production. Similarly, excessive ER-β \nreceptors in the endothelial cells of the uterine micro -\nvasculature induce cyclooxygenase (COX) and prosta -\nglandin-E2  (PGE2) [72]. This indicates the therapeutic \nsignificance of the regulation of receptor expression.\nA genetic component has a strong association with \nendometriosis. Single nucleotide polymorphism (SNP) in \na gene decides the role of the gene in a disease [73]. FSHB \nlocus with SNP rs11031006 is associated with increased \nmenstrual cycle length and decreased endometriosis risk \n[74], whereas FSHB/11p14.1 with SNP rs4071559 is asso-\nciated with endometriosis as well as uterine leiomyomata \n[22, 73].\nDifferent genes with SNP have been identified which \nincrease the susceptibility to endometriosis. Some results \nwere conflicting. However, a recent study has identified \nspecific genes with their SNP to be the predisposing fac -\ntor. These include fibronectin 1 (FN1 rs1250248), wing -\nless-type mammalian mouse tumor virus integration site \nfamily member 4 (WNT4  rs7521902), growth regula -\ntion by estrogen in breast cancer 1 (GREB1 rs13394619), \nvezatin (VEZT  rs10859871), and interleukin-1 alpha \n(IL1A rs6542095) [75]. Other SNPs of IL1A associated \nwith endometriosis include rs6542095, rs11677416, \nrs3783550, rs3783525, rs3783553, rs2856836, rs1304037, \nand rs17561 [76]. These genes play their roles in dif -\nferent pathways. FN1 rs1250248 is implicated in the \nangiogenic pathway, WNT4  rs7521902 in embryonic \ndevelopment, GREB1 rs13394619 in the hormonal path -\nway, VEZT rs10859871 in cytoskeleton regulation [75], \nand IL1A rs6542095 in various immune responses and \ninflammatory pathways [76]. FN1 rs1250248 increases \nthe expression of angiogenesis-related proteins such as \nvascular endothelial growth factor (VEGF), cluster of dif -\nferentiation 31 (CD31), TEK tyrosine kinase (Tie2), and \nVe-cadherin through WNT-inducible signaling pathway \nprotein-3 (WISP-3). FN1 rs1250248 elevates WISP-3 \nexpression via focal adhesion kinase/mitogen-activated \nprotein kinase/hypoxia-inducible factor 1-alpha (FAK/\nMAPK/HIF-1α) axis. This axis is known to promote \ntumor angiogenesis [77]. FAK is known for its cancer-\npromoting role through extracellular signal-regulated \n\nPage 6 of 27Paul et al. Middle East Fertility Society Journal            (2025) 30:6 \nkinase (ERK)−1/2 signaling [78]. ERK/MAPK pathway \ninhibits granulosa cell proliferation in endometrio -\nsis and affects the growth and development of oocytes \n[79]. MAPK pathway regulates the activation of nuclear \nfactor kappa B (NF-kB) [80]. NF‐kB increases the tran -\nscription of HIF‐1α in response to many pathological \nconditions such as hypoxia and bacterial invasion [81]. \nNF-kB activation in macrophages and ectopic endo -\nmetrial cells leads to the synthesis of proinflammatory \ncytokines, which leads to the formation of endometri -\notic lesions [82]. NF-kB links chronic inflammation to \ncancer [83]. Similarly, HIF-1α can induce endometriotic \nlesions [84, 85]. This indicates that FN1 rs1250248 may \ninitiate endometriotic lesions through FAK/ERK/MAPK/\nNF-kB/HIF-1α/WISP-3 pathway. This shows a com -\nmon pathway between endometriotic lesions and cancer. \nAnother pathway implicated in endometriotic lesions is \nthe nuclear factor erythroid 2-related factor 2 (Nrf2)/\nkelch-like ECH-associated protein 1(Keap1)/heme oxy -\ngenase 1 (HO1) axis. The endometriotic lesion shows a \nsignificant increase in Nrf2 and HO-1 and a decrease in \nKeap1. Keap1 has a suppressing role on Nrf2 [86], and it \nis the key negative regulator of Nrf2 [87]. It is notewor -\nthy that endometriotic lesions show higher expression of \nVEGF, its receptor VEGFR-2, matrix metalloproteinase-9 \n(MMP-9), and activated macrophages (ED-1 positive \ncells). A positive correlation has been reported between \nVEGF and ED-1 expression [88]. Activated macrophages \nderived from the endometrium are responsible for the \nendometriotic lesions rather than macrophages derived \nfrom the peritoneal cavity [89]. Similar expression pat -\ntern of VEGF, VEGFR-2, and MMP-9 was observed \nin both endometriosis and cancer diseases including \novarian cancer [88, 90]. Previous studies have already \nproved the association between higher expression lev -\nels of MMP-9 and higher degree/stage of endometrio -\nsis [91]. This unveils the presence of a hidden ovarian \ncancer aggravating mechanism in the pathophysiologi -\ncal path of endometriosis [90]. Other MMPs which are \ncrucial for the invasion of endometrial cells and vascu -\nlarization in endometriosis include MMP-1, MMP-2 \n[92], and MMP-3 [93–95]. SNP of MMP3 276A allele is \na risk factor for advanced endometriosis and infertility \n[95]. Another SNP that is associated with endometriosis \nin Greek women includes rs11556218 of the IL-16 gene \n[96]. Similarly, a different SNP rs4778889 of IL-16 is asso-\nciated with endometriosis in Nigerian [97] and Chinese \nwomen [98]. This proves the role of ethnic variation in \nthe involvement of different SNPs of the same gene in the \npathogenesis of endometriosis.\nThe five most significant gene polymorphisms asso -\nciated with endometriosis include interferon gamma \n(IFNG) (CA) repeat, glutathione S-transferase mu 1 \n(GSTM1) null genotype, glutathione S-transferase pi 1 \n(GSTP1) rs1695, and WNT4  rs16826658 and rs2235529 \n[99, 100]. Contrary to this, another finding reveals that \nWNT4 rs16826658 including rs7515106 and rs7521902 \nwere not associated with endometriosis, but WNT4  \nrs2235529 was associated with endometriosis [101]. \nHowever, a recent study claims an association between \nWNT4 rs7521902 and endometriosis [75]. Similarly, \nanother study shows that there was no difference in the \nfrequencies of GSTM1 polymorphism (null genotype) \nbetween endometriosis cases and controls in Brazil -\nian women. However, polymorphism (null genotype) \nof theta (θ) of the glutathione S-transferase system 1 \n(GSTT1) was predominantly observed in the endome -\ntriosis group than in the control group [102]. Six other \npolymorphisms of interest in the setting of endome -\ntriosis include progesterone receptor (PGR) PROGINS, \nintercellular adhesion molecule 1 (ICAM1) rs1799969, \naryl-hydrocarbon receptor repressor (AHRR) rs2292596, \ncytochrome family 17 subfamilies A polypeptide 1 \n(CYP17A1) rs743572, CYP2C19 rs4244285, and peroxi -\nsome proliferator-activated receptor gamma (PPARG ) \nrs1801282 [99]. Some polymorphisms may not have any \nlink with the development of the disease but can influ -\nence the stage of the disease. Polymorphism of PvuII and \nXbaI in estrogen receptor (ESR1/ER-α) is associated with \nstage I to III endometriosis but has no correlation with \nthe development of endometriosis [103]. Other risk fac -\ntors such as SNP (rs1042522) of tumor suppressor gene \np53 may increase the risk of endometriosis [104]. Simi -\nlarly, ovarian endometriosis is linked with MAP kinase-\ninteracting serine/threonine-protein kinase 1 (MKNK1) \nand DNA topoisomerase III alpha (TOP3A). MKNK1 \nfavors ectopic endometrial stromal cell (EESC) migration \nand invasion, whereas TOP3A favors the proliferation \nof EESC [105]. Irrespective of many established genetic \nassociations of endometriosis, it was proved that the \nassociation between genetic polymorphism and endo -\nmetriosis is subject to ethnic variation [101]. Neverthe -\nless, genetic association with endometriosis should not \nbe overlooked due to the vulnerability of that particular \nethnic population.\nRecent studies have implicated RNA in the pathogen -\nesis of endometriosis. The expression level of long non-\ncoding RNA (lncRNA) was much higher in the ectopic \nendometrium compared to the eutopic endometrium \nin the majority of cases [106]. lncRNAs can promote \ncell migration and metastasis. They reduce apoptosis \nrate [107]. However, overexpression of certain types of \nlncRNA such as maternally expressed gene 3 (MEG3) \nplays a protective role by preventing endometrial cell \nproliferation and invasion [108]. Similar to lncRNA, \nanother type of non-protein-coding transcript that plays \n\nPage 7 of 27\nPaul et al. Middle East Fertility Society Journal            (2025) 30:6 \n \na role in endometriosis is microRNA (miRNA). lncRNA \nand miRNA have been found to control inflammatory \nresponses, cell proliferation, and angiogenesis [106]. \nlncRNA HOTAIR favors the invasion and migration of \nendometrial stromal cells by acting on multiple miR -\nNAs [109]. miRNAs can also facilitate metastasis. Peri -\ntoneal macrophage-derived exosomal miR-22-3p plays \nan important role in EESC proliferation, migration, and \ninvasion. miR-22-3p targets sirtuin 1 (SIRT1) [110], a \nclass III histone deacetylase. This will abolish the sup -\npressing effect of SIRT1 on NF-kB expression, leading to \nan increased NF-kB activity [111]. NF-kB activation in \nmacrophage and ectopic endometrial cells will trigger the \nsynthesis of proinflammatory cytokines; this will estab -\nlish, maintain, and develop endometriotic lesions. NF-kB \nactivation is implicated in “cell adhesion, invasion, angio-\ngenesis, inflammation, proliferation, and apoptosis” [82]. \nContextually, miR-202-3p, miR-411-5p, miR-29c-3p, and \nmiR-138-5p were upregulated in peritoneal implants and \nrectovaginal lesions [112]. Other microRNAs of clini -\ncal significance are miR-95, miR-103, miR-106a, miR-\n151, miR-155, miR-182, miR-183, miR-194, miR-200a, \nmiR-200c, miR-203, miR-205, miR-210, and miR-223. \nExpression levels of these microRNAs were higher in \nendometrioid endometrial adenocarcinoma in Chinese \nfemales. Among these miRNAs, miRNA 205 had a very \nhigh expression level and has been correlated with inva -\nsion into muscle layers and recurrence [113, 114]. The \nsignificance of these miRNAs is evident from the finding \nthat endometriosis has a strong correlation with endome-\ntrioid adenocarcinoma [115]. Other miRNAs which play \na role in endometriosis include miR-616-3p, miR-21-5p, \nand miR-194-3p. miR-616-3p favors cell proliferation and \nmigration in endometriosis when downregulation of cir -\ncular RNA (circ RNA) such as circ_0000673 occurs [116]. \nmiR-21-5p plays a role in downregulating progesterone \nreceptor expression [117]. The endometrium of patients \nwith endometriosis shows significant upregulation of \nmiR-21-5p [118]. Similarly, miR-194-3p is responsible for \nprogesterone resistance and infertility in endometriosis \npatients [119].\nDysregulation of the pro-inflammatory pathway plays \na critical role in endometriosis. Endometrioma tran -\nscriptome analysis identifies epithelium, stroma, and \nproximal mesothelial cells to be the primary sites of dys -\nregulation [120]. Cytokines play an important role in the \npro-inflammatory pathway involved in endometriosis. \nCytokines which are implicated in endometriosis include \nIL-1β, IL-6, IL-10, IL-15, IL-16, IL-17A, IL-18, IL-27, \nIL-33, IL-37, TNF-α, NF-kB, and monocyte chemotactic \nprotein-1 (MCP-1) [18, 120]. IL-1β can induce cyclooxy -\ngenase-2 (COX-2) by favoring the phosphorylation of \nERK, p38, and Jun N-terminal kinase (JNK). COX-2 is \nresponsible for “cell proliferation, a low level of apoptosis, \nhigh invasion, angiogenesis, endometriosis-related pain, \nand infertility” . COX-2 will produce  PGE2;  PGE2 will pro-\nmote endometriosis by binding with EP2 and EP4 recep -\ntors. The pathological significance of COX-2 and  PGE2 is \nevident from their higher levels in endometriotic lesions \ncompared to normal endometrium [121]. Similarly, \nTNF-α and IFN-γ synergistically trigger COX-2 produc -\ntion in macrophages [122] and the role of macrophages \nin endometriosis is well documented [82, 89]. IL-1β along \nwith IL-12 can induce the IFN-γ gene and increase the \nIFN-γ protein level in CD56 (bright), a subset of NK cells \n[123]. It is found that the presence of endometriosis or \nits stage has no impact on the concentration of peritoneal \nIL-12 [124]. Interestingly, murine model study shows that \nIL-12 inhibits ectopic endometriotic tissue development \nin the peritoneal cavity via NK cell activation [125].\nIL-1β disrupts the decidual function in human endo -\nmetrial stromal cell cultures obtained from normal \ncontrol and from eutopic endometrium of patients with \nendometriosis. This was accompanied by rapid phos -\nphorylation of estrogen receptor ER-α, progesterone \nreceptors A and B, gap junction protein, and connexin \n(Cx)43—leading to their cellular depletion. This will \nlead to decreased fertility in women [126]. IL-1β and \nIL-6 have been identified to cause neuroangiogenesis in \nendometriosis [127]. Studies have found a significantly \nhigher serum concentration of IL-1β, IL-6, and TNF-α \nin women with endometriosis [128]. IL-1β was signifi -\ncantly higher in endometriotic tissue compared to the \nendometrium of the patient with endometriosis or \nhealthy control. Similarly, endometrioma had shown a \nhigher level of IL-1β compared to lesions of other local -\nizations. However, IL-6 was prevalent in both endome -\ntriotic tissue and endometrium of patients with \nendometriosis. Strangely, the TNF-α level was signifi -\ncantly lower in endometriotic tissue compared to the \nendometrium of the healthy control [129]. This shows a \nlocation-specific prevalence of these cytokines in endo -\nmetriosis. The significance of location specificity is \napparent from the finding that higher serum concentra -\ntion of IL-6 and/or IL-8 is associated with infertility \namong endometriosis patients [130]. Ectopic endome -\ntrium shows a significantly higher concentration of \nIL-15 but the eutopic endometrium shows a higher \nconcentration of IL-7 [131]. IL-15 expressed by endo -\nmetrial stromal cells downregulates granzyme B and \nIFN-γ in  CD16+NK cells. This will prevent the killing \nactivity of NK cells; favor invasiveness, maintain viabil -\nity, and trigger the proliferation of endometrial stromal \ncells [132]. IFN-γ level and IFN-γ +CD4+ percentage in \nthe peritoneal fluid were significantly higher in both \nearly and advanced stages of endometriosis. The \n\nPage 8 of 27Paul et al. Middle East Fertility Society Journal            (2025) 30:6 \nadvanced stage of endometriosis also shows elevated \nlevels of IL-10 and IL-10 +CD4+ cells. In this regard, it \nis noteworthy that IL-27 overexpressing endometrial \nstromal cells and macrophages induces an excess of IL-\n10+CD4+ T cells. IL-27 and IL-2 play a synergistic role \nin promoting the growth and invasion of ectopic \nendothelial stromal cells by modulating IFN-γ and \nIL-10. Even the transcription of enzymes of ectopic \nendothelial stromal cells such as MMP-2, MMP-9, and \nprostaglandin-endoperoxide synthase 2 will be pro -\nmoted [133]. This raises concern due to the fact that \nMMP-2 plays a role in endometrial cancer. Its expres -\nsion shows a close association with clinical stage, tumor \ninvasion, and metastasis [134– 136]. Similarly, MMP-9 \nis highly expressed in endometrial cancer [136]. IL-27 \npromotes IL-10 production by T helper cell 17 (Th17) \nby c-musculoaponeurotic fibrosarcoma (c-Maf)/reti -\nnoic acid-related orphan receptor gamma t (RORγt)/B \nlymphocyte-induced maturation protein-1 (Blimp-1) \npathway. This leads to the progression of endometriosis \n[137]. Recent studies have also proved the pro-fibrotic \nrole of IL-10 in endometriosis which includes “cell pro -\nliferation, collagen type I synthesis, α-smooth muscle \nactin positive stress fibers, and collagen gel contrac -\ntion” [138]. Previous studies have also proved the role \nof IL-10 in the development of endometriosis [139]. \nAnother cytokine that has an active role in endometrio -\nsis is IL-16. It is associated with severe chronic pelvic \npain in endometriosis. Serum concentration of IL-16 \nsignificantly increases as there is a shift from mild pain \nto chronic severe pain. This indicates a positive correla -\ntion between IL-16 concentration and pelvic pain [97, \n98]. Peritoneal fluid from patients with advanced stage \n(III/IV) endometriosis shows a significantly higher \nIL-16 concentration compared to normal control. Peri -\ntoneal IL-16 can induce the release of cytokines, such \nas IL-6, TNF-α, and IL-1β, from peritoneal fluid mono -\nnuclear cells (PFMC)—leading to inflammatory mani -\nfestations [140]. In this regard, it is worth mentioning \nthat IL-6 may have regenerative and anti-inflammatory \nroles via classic signaling, where only a few cells express \nIL-6 receptors. At the same time, IL-6 will also have a \npro-inflammatory role via trans-signaling where solu -\nble IL-6 receptors can stimulate any cell type [141]. \nAnother cytokine implicated in the pathogenesis of \nendometriosis is IL-17A. Peritoneal fluid and plasma \nshow a higher concentration of IL-17A compared to \nnormal control [142, 143]. Elevated levels of IL-17A in \nserum and follicular fluid have some correlation with \nendometriosis and infertility. The stroma and the sur -\nroundings of the vasculature show higher concentra -\ntions of IL-17A in eutopic endometrium and ectopic \nlesions. IL-17A favors angiogenesis through VEGF and \nIL-8 and promotes inflammation through IL-6 and \nIL-1β [142, 144]. IL-8 partly favors the action of angi -\nopoietin-1 (Ang-1) in promoting endothelial migration \nand proliferation [145]. It is noteworthy that VEGF \noverexpression favors neovascularization accompanied \nby plasma leakage but Ang-1 overexpression favors \nenlargement of existing blood vessels without favoring \nplasma leakage [146]. The significance of Ang-1 is evi -\ndent from the finding that eutopic endometrium from \nwomen with endometriosis shows higher mRNA and \nprotein expression of Ang-1 (P  < 0.05) compared to the \nendometrium without endometriosis. Even the mRNA \nlevel of Ang-2 was significantly higher in the eutopic \nendometrium of patients with endometriosis. Increased \nexpression of Ang-1 mRNA, Ang-2 mRNA, and Ang-1 \nprotein makes eutopic endometrium more angiogenic \n[147]. However, the Ang-2 protein opposes the func -\ntion of Ang-1 and has an inhibitory effect on angiogen -\nesis [148]. Contextually, IL-1β and IL-23 can stimulate \nthe release of IL-17 [149, 150] and the peritoneal fluid \nof endometriosis patients shows a higher level of IL-23 \n[151]. This shows the significance of a higher level of \nIL-23 in the peritoneal fluid, though the serum level of \nIL-23 in the endometriosis group was lower than in the \nnon-endometriosis group [152]. The actual role of \nIL-23 in the context of endometriosis remains elusive \ndue to the fact that IL-23 decreases IL-8 secretion. \nDecreased IL-8 level is believed to reduce endometrial \nstromal cell viability [153]. This shows that suppression \nof IL-8 will alleviate endometriosis because excessive \nstromal cell viability is a favoring factor for endometri -\nosis [154, 155]. However, the complexity of the role of \nIL-23 further increases from the consideration that an \nincreased level of IL-23 may be the reason behind infer -\ntility in endometriosis patients [151]. Another cytokine \nimplicated in endometriosis is IL-18. Peritoneal fluid \nfrom endometriosis patients shows a higher concentra -\ntion of IL-18 compared to non-endometriotic samples. \nThis is related to the consequent activation of cyclooxy -\ngenase-II in peritoneal monocytes. This is linked with \nthe pathogenesis of endometriosis [156]. Contrary to \nthis finding, a contemporary observation reveals a \nlower concentration of IL-18 in the peritoneal fluid of \nendometriosis patients compared to the control group. \nStrangely, this is also related to the pathogenesis of \nendometriosis [157]. Another research shows that \npatients with minimum or mild endometriosis did not \nshow increased levels of peritoneal and serum IL-18 \n[158]. Another cytokine that plays a role in the patho -\ngenesis of endometriosis is IL-33. Both plasma and per -\nitoneal levels of IL-33 are associated with deep \nendometriosis. IL-33 plays a significant role in inflam -\nmation, angiogenesis, and proliferation of lesions. The \n\nPage 9 of 27\nPaul et al. Middle East Fertility Society Journal            (2025) 30:6 \n \ninvasiveness of human endometriotic stromal cells \nthrough membrane-bound IL-33 receptor (ST2)/\nMAPK/MMP-9 pathway is also promoted by IL-33. \nIL-33 induces the production of profibrotic cytokines \nby regulatory T cells and promotes fibrogenesis [159–\n162]. Another cytokine implicated in the pathogenesis \nof endometriosis is IL-37. It is known for its anti-\ninflammatory role. It inhibits adhesion, migration, and \ninvasion of endometrial stromal cells and also sup -\npresses the activity of MMP-2 and MMP-9. It also sup -\npresses IL-1β, IL-6, IL-10, and TNF-α [163]. Contrary \nto this, one study has found a positive correlation \nbetween IL-37 and TNF-α levels in the peritoneal fluid \nof patients with endometriosis; the expression levels of \nboth IL-37 and TNF-α were higher in endometriosis \npatients compared to the control group [164]. This \nraises concern about the actual implication of IL-37 in \nendometriosis because TNF-α stimulates the prolifera -\ntion of endometrial cells and favors angiogenesis. The \nlevel of soluble TNF-α receptor-I was higher in all \nstages of endometriosis; indicating the pathological \nrole of soluble TNF-α receptor-I in endometriosis \n[165]. Another cytokine that takes part in the patho -\ngenesis of endometriosis is MCP-1. The follicular fluid \nof infertile patients with endometriosis shows a signifi -\ncantly higher concentration of MCP-1 mRNA along \nwith other cytokines such as TNF-α and IL-10. This \nindicates their involvement in endometriosis as well as \ninfertility [166]. Studies have proved a significantly \nhigher concentration of MCP-1 in serum and perito -\nneal fluid along with hepatocyte growth factor (HGF) \nand insulin-like growth factor-1 (IGF-1). Peripheral \nblood mononuclear cells (PBMC), PFMC, and EESC \nhave shown significantly higher levels of MCP-1  and \nIGF-1 gene expression. MCP-1 and IGF-1 protein \nexpression by PFMCs was significantly higher in endo -\nmetriotic women compared to the control group. HGF \ngene and HGF protein expression by PFMC were sig -\nnificantly higher in endometriotic women compared to \ncontrol. Similarly, gene expression of HGF by EESC was \nsignificantly higher in endometriotic women [167]. \nHGF promotes the proliferation and invasion of stro -\nmal cells. This is partly facilitated by urokinase-type \nplasminogen activator [168]. Similarly, IGF-1 favors \nendometriosis by stimulating the growth of endome -\ntrial cells and preventing their apoptosis. IGF-1 signal -\ning is also responsible for hyperalgesia [169].\nOther mediators of endometriosis include fibrino -\ngen and leptin. Fibrinogen alpha chain concentration in \nserum and its expression level by the endometrial tissue \ndetermine the severity of the pathogenesis of endome -\ntriosis. A positive correlation has been observed between \nfibrinogen alpha chain concentration and endometriosis \n[170]. Similarly, higher leptin concentrations in the peri -\ntoneal fluid and follicular fluid of women with endome -\ntriosis are suggested to play a role in endometriosis [171]. \nThe murine model study has proved that a deficiency of \nleptin and its receptor can suppress endometriosis [172]. \nAll these molecular targets (Table  1) together can aggra -\nvate the disease condition. The druggable molecular tar -\ngets are shown in Fig. 1.\nPlants in the management of endometriosis\nNature with its variety of plants has the potential to treat \nmany diseases. Modern technology of identification and \nisolation of phytoconstituents from plant sources has \nemerged as a promising alternative to treat many disor -\nders. Different phytoconstituents which can target the \nmediators of endometriosis and alleviate the disease are \nmentioned below.\nPhytoconstituents acting as progestin and modulating \nprogesterone receptor B\nPhytoprogestins such as apigenin (a flavonoid) and \nkaempferol (a flavonoid) show progestogenic activity. \nThey upregulate zinc finger and BTB domain-containing \n16 (ZBTB16) expression. Apigenin significantly (p < 0.05) \nincreases the level of ZBTB16 protein [173]. ZBTB16 \nexpression is required for decidualization, a step cru -\ncial for pregnancy [174]. Apigenin shows progesterone \nreceptor B modulatory activity. It has mixed progester -\none receptor agonist activity and can suppress estrogen \nreceptor-mediated uterine proliferation [175]. Apigenin \nshows a potent anti-angiogenic effect and can reduce \nmicrovessel density [176]. Apigenin can suppress the pro-\nliferation and induce apoptosis of endometriosis cell lines \nsuch as VK2/E6E7 and End1/E6E7. Apigenin has induced \ndysregulation of mitochondrial membrane potential. \nThis led to an increase in cytosolic calcium. Calcium \nand other pro-apoptotic proteins such as Bax, Bak, and \ncytochrome C have induced apoptosis in VK2/E6E7 cells. \nHowever, apoptosis of End1/E6E7 cells was triggered by \nBax and cytochrome C. Apigenin is also found to possess \nan anti-inflammatory effect [177]. This shows the pos -\nsibility and significance of Apigenin in the treatment of \nendometriosis because progesterone-mediated healing of \nendometriosis involves inhibition of angiogenesis, uter -\nine cell proliferation, and inflammation [178] (Table 2).\nPhytoconstituents acting as estrogen and targeting ER‑β\nPhytoestrogens such as genistein and coumestrol (iso -\nflavonoids) have a higher affinity for ER-β compared to \nER-α. Genistein shows a 30-fold higher relative estro -\ngenic potency on ER-β compared to the potency on ER-α. \nSimilarly, coumestrol shows a higher binding affinity \nfor ER-β receptors [179]. The murine model study has \n\nPage 10 of 27Paul et al. Middle East Fertility Society Journal            (2025) 30:6 \nTable 1 Molecular/therapeutic target for the treatment of endometriosis\nTherapeutic target Role in endometriosis Reference\nProgesterone receptor A Inhibits progesterone receptor B expression, negative regulation \nof progesterone receptor B, endometrial hyperplasia, chronic \npelvic pain, infertility, inflammatory disorders, and cancer\n[62, 63, 65, 66]\nProgesterone receptor B Prevents endometrial hyperplasia and inflammation [62]\nER-α receptor Endometrial proliferation, pain, recurrence, and endometrial \ncancer\n[69, 70, 71]\nER-β receptor Opposing effect on the function of ER-α receptor [70, 182, 184]\nmiR-194-3P Progesterone resistance and infertility [119]\nmiR-21-5p and lncRNA Inflammatory responses, cell proliferation, angiogenesis, cell \nmigration, and reduced apoptosis\n[106, 107, 118]\nlncRNA MEG3 Prevents endometrial cell proliferation and invasion [108]\nlncRNA HOTAIR Favors invasion and migration of endometrial stromal cells \nthrough miRNAs\n[109]\nmiR-95, miR-103, miR-106a, miR-151, miR-155, miR-182, miR-\n183, miR-194, miR-200a, miR-200c, miR-203, miR-205, miR-210 \nand miR-223\nInvasion into muscle layers, recurrence, endometrioid adeno-\ncarcinoma\n[113, 114, 115]\nmiR-202-3P , miR-411-5P , miR-29c-3P , miR-138-5P Peritoneal implant and rectovaginal lesions [112]\nmiR-616-3p Favors cell proliferation and migration in endometriosis [116]\nVEGF, CD31, Tie2, Ve-cadherin, FAK/MAPK/HIF-1α axis Angiogenesis [77, 84, 85]\nAng-1 mRNA and protein, Ang-2 mRNA Eutopic endometrium angiogenesis [147]\nHIF-1α Endometriotic lesions [84, 85]\nNrf2/Keap1/HO1 axis Endometriotic lesions [86]\nNF-kB Synthesis of proinflammatory cytokines and formation of endo-\nmetriotic lesion\n[82]\nMMP-1 Invasion of endometrial cells and vascularization [92]\nMMP-2 Endometriosis and endometrial cancer [134, 135, 136, 163]\nMMP-3 Invasion of endometrial cells, vascularization, advanced endo-\nmetriosis, and infertility\n[93, 94, 95]\nMMP-9 Endometriosis and cancer diseases including ovarian cancer \nand endometrial cancer\n[88, 90, 91, 136]\nMKNK1 EESC migration and invasion [105]\nTOP3A Proliferation of EESC [105]\nIL-1β, IL-6, IL-10, IL-15, IL-16, IL-17A, IL-18, IL-27, IL-33, IL-37, TNF-α, \nMCP-1\nInflammation [18, 120]\nIL-1β, IL-6 and IL-8 Infertility associated with endometriosis [126, 130]\nIL-2 and IL-27 Growth and invasion of EESC increases transcription of enzymes \nof EESC such as MMP-2, MMP-9, and prostaglandin-endoperox-\nide synthase 2\n[133]\nIL-10 Pro-fibrotic role and promotes endometriosis [138, 139]\nIL-15 Invasiveness, viability, and proliferation of endometrial stromal \ncell\n[132]\nIL-16 Severe pain in endometriosis [97, 98]\nIL-17A Angiogenesis through VEGF and IL-8 promotes inflammation \nthrough IL-6 and IL-1β\n[142, 144]\nIL-33 Inflammation, angiogenesis, proliferation of lesions, invasiveness \nof human endometriotic stromal cell, production of profibrotic \ncytokines\n[159, 160, 161, 162]\nCOX-2,  PGE2, EP2 and EP4 receptors Cell proliferation, apoptosis (low level), high invasion, angiogen-\nesis, endometriosis-related pain and infertility\n[121]\nIFN-γ, TNF-α COX-2 induction, endometrial cell proliferation, and angiogen-\nesis\n[122, 165]\nMCP-1 Inflammatory changes in endometriosis, infertility [166, 167]\nHGF, urokinase-type plasminogen activator Proliferation and invasion of stromal cells [167, 168]\nIGF-1 Endometrial cell growth prevents endometrial cell apoptosis \nand hyperalgesia\n[167, 169]\n\nPage 11 of 27\nPaul et al. Middle East Fertility Society Journal            (2025) 30:6 \n \nproved that genistein has significantly (P < 0.05) reduced \nthe expression of ER-α receptor, but there was a signifi -\ncant (P < 0.05) increase in the expression of ER-β in peri -\ntoneal endometriosis [180]. Alaria, a seaweed can lower \nestrogen levels in the body, reducing the risk of endome -\ntriosis [181].\nPhytoconstituents targeting MAPK pathway, MKNK1, \nand TOP3A\nQuercetin (a flavonoid) significantly decreases endo -\nmetriotic cell proliferation by suppressing the phospho -\nrylation of p38MAPK/ERK-1/2/phosphatidyl inositol-3 \nkinase (PI3K)/protein kinase B (AKT). It also causes a \ndecrease in the expression of cyclin D1, which plays a \nrole in cell proliferation [182]. The anti-proliferation \nmechanism is somewhat complicated because p38MAPK \nis known to negatively regulate cyclin D1 [183]. Never -\ntheless, it has proved its role as an anti-proliferation \nagent. It induces cell apoptosis by destroying mitochon -\ndrial membrane potential and inducing DNA fragmen -\ntation. It generates reactive oxygen species (ROS) and \ncauses lipid peroxidation of the proliferating cells, lead -\ning to apoptosis. Quercetin also reduces the size of endo -\nmetriotic lesions [182]. It also activates the ER-β receptor \nto interrupt the endometrial proliferative role of the ER-α \nreceptor [182, 184]. The best part of quercetin is that it is \nsafe for normal cells [182]. Similarly, curcumin (a poly -\nphenol) is also an AKT inhibitor [185]. Genistein can \ndownregulate MAPK activation [186]. The network anal -\nysis technique suggests that ursolic acid may target the \nTable 1 (continued)\nTherapeutic target Role in endometriosis Reference\nFibrinogen alpha chain Severity of pathogenesis of endometriosis [170]\nLeptin and its receptor Favors endometriosis [171, 172]\nFig. 1 Molecular targets for the treatment of endometriosis\n\nPage 12 of 27Paul et al. Middle East Fertility Society Journal            (2025) 30:6 \nTable 2 Phytoconstituents effectively regulating the molecular targets\nTherapeutic target Phytoconstituents of therapeutic significance Reference\nProgesterone receptor B Apigenin modulates progesterone receptor B [175]\nER-α receptor Genistein significantly reduces the expression of the ER-α \nreceptor\n[180]\nER-β receptor Genistein significantly increases the expression of the ER-β \nreceptor\n[180]\nmiR-21-5p and lncRNAs Saponins significantly decrease miR-21 −5p expression. Res-\nveratrol can increase and decrease the expression of lncRNAs \nsuch as MEG3 and H19, respectively\n[108, 118, 196]\nlncRNA HOTAIR Xiaoji decoction significantly decreases lncRNA HOTAIR \nexpression\n[203]\nmiR-95 Genistein can downregulate miR-95 [190, 191]\nmiR-103 Anthocyanins, flavonols, and derivatives of phenolic acids can \nreduce miR-103 expression\n[192]\nmiR-223 Genistein downregulates miR-223 [194, 195]\nmiRNA 155, miRNA 138 Curcumin significantly decreases the miRNA expression levels \nof miRNA 155 and miRNA 138\n[189]\nmiR-183 Gleditsia sinensis extract significantly suppresses miR-183 [193]\nVEGF, CD31, Tie2, FAK/MAPK/HIF-1α axis Resveratrol decreases VEGF expression; Apigenin strongly \nsuppresses VEGF-A/VEGFR2 pathway; Polysaccharide \nfrom Lentinus edodes downregulates CD31 expression; \n5α-hydroxycostic acid and hydroxyisocostic acid inhibit Tie-2 \nphosphorylation; Quercetin suppresses p38MAPK/ERK-1/2/ \nPI3K/ protein kinase B (AKT); Apigenin strongly suppresses \nHIF-1α\n[176, 182, 202, 204, 205]\nAng-1 mRNA and protein Resveratrol decreases Ang-1 mRNA [202]\nAng-2 mRNA 5α-hydroxycostic acid and hydroxyisocostic acid can suppress \nAng-2 mRNA expression\n[205]\nNrf2/Keap1/HO1 axis Naringenin decreases the expression of Nrf2 and HO1 \nbut increases Keap1 expression\n[86]\nMMP-1, MMP-2, MMP-3, MMP-9 Kaempferol significantly decreases MMP-1 and MMP-3 \nprotein expression; Curcumin pretreatment inhibits MMP-2 \nactivity; Withaferin-A downregulates the expression of MMP-2 \nand MMP-9; Quercetin can suppress MMP-2 and MMP-9; \nNaringenin suppresses both MMP-2 and MMP-9, Resveratrol \nreduces MMP-2; Genistein inhibits the production and activity \nof MMP-2 and MMP-9\n[86, 186, 202, 206, 207, 219, 222, 223]\nMKNK1 Ursolic acid targets MKNK1 and may prevent EESC migration \nand invasion\n[187]\nTOP3A Shogaol, demethoxycurcumin, capsaicin, ellagic acid, 6‐para-\ndol, 6‐gingerol, carnosic acid, and curcumin act as antago-\nnists for human DNA TOP3A\n[188]\nIL-1β, IL-2, IL-6, IL-8, IL-10, IL-17A, IL-18, IL-33, \nTNF-α, NF-kB, IFN-γ, MCP-1\nWithaferin-A reduces the levels of IL-1β, IL-6, TNF-α and down-\nregulates NF-kB signaling; Resveratrol suppresses IL-8 release; \nQuercetin and tuberostemonine-O can significantly inhibit \nIL-2 production; Quercetin significantly reduces protein \nlevel and gene expression of IFN-γ; Apigenin decreases \nIL-10 and TNF-α expression; Rosmarinic acid can suppress \nthe production of IL-17A; Curcumin can significantly suppress \nIL-18 production; Licochalcone-A suppresses IL-1β and IL-18 \nexpression; Apigenin and luteolin suppress the production \nof IL-33; Quercetin suppresses MCP-1 mRNA and protein \nexpression levels\n[206, 208, 209, 210, 211, 212, 213, 214, 215]\n\nPage 13 of 27\nPaul et al. Middle East Fertility Society Journal            (2025) 30:6 \n \nMKNK1 gene and prevent EESC migration and invasion \n[187]. In silico studies have proved that “shogaol, dem -\nethoxycurcumin, capsaicin, ellagic acid, 6‐paradol, 6‐\ngingerol, carnosic acid, and curcumin” can bind strongly \nwith human DNA TOP3A and act against TOP3A [188] \n(Table 2).\nPhytoconstituents targeting miRNA\nSaponins (glycosides of triterpenes and steroids) can sig -\nnificantly (p = 0.022) decrease miR-21 −5p expression \nin human endometriotic stromal cells. This will sup -\npress the proliferation and also induce the apoptosis of \nendometriotic cells by unleashing caspase-3. Saponins \ncan significantly (p < 0.05) induce caspase-3 expression \n[118]. Curcumin has been found to significantly decrease \nthe miRNA expression levels of miRNA 155 (P = 0.002), \nmiRNA 138 (P = 0.024), and miRNA16 (P = 0.0001) [189]. \nGenistein can downregulate miR-95 [190, 191]. A com -\nbination of polyphenols such as anthocyanins, flavonols, \nand derivatives of phenolic acids can reduce the expres -\nsion of miR-103 [192]. Extract of Gleditsia sinensis can \nsignificantly (P < 0.01) suppress the expression of miR-\n183 [193]. Genistein can also downregulate the expres -\nsion of miR-223 [194, 195] (Table 2).\nPhytoconstituents targeting lncRNA\nResveratrol at 200  µM concentration can increase the \nexpression of several lncRNAs such as MEG3, pituitary \ntumor-transforming 3 pseudogene (PTTG3P), BST2 \ninterferon-stimulated positive regulator (BISPR). Res -\nveratrol at 50 µM concentration can increase lncRNAs \nsuch as metastasis-associated lung adenocarcinoma \ntranscript 1 (MALAT1) and conserved gene cluster H19 \nlocus (H19) but at 200 µM concentration can decrease \nthe expression of H19. Similarly, the expression of \ngrowth arrest-specific transcript 5 (GAS5) was sig -\nnificantly decreased. A decreased expression of H19 \nhas been beneficial in inducing apoptosis and death of \ncancer cells [196]. MEG3 stops endometrial cell prolif -\neration and invasion [108]. Thus, the beneficial role of \nresveratrol seems to be partly dependent on its mod -\nulating effects on the expression levels of MEG3 and \nH19. The actual role of resveratrol is much more com -\nplicated because the expression level of BST2 is very \nhigh in ectopic endometrium. BST2 is responsible for \nEESC proliferation, migration, and lymphangiogen -\nesis during endometriosis. BST2 also inhibits apoptosis \n[197]. Similarly, MALAT1 is responsible for the sur -\nvival of endometrial stromal cells under hypoxic condi -\ntions. Hypoxia induces HIF‐ 1α, and HIF-1α upregulates \nMALAT1 [198]. GAS5 can suppress NF-kB [199] and \nrepresses endometrial cancer [200]. H19 is responsible \nfor infertility, endometriosis, uterine fibroids, and many \nother disorders [201]. Thus, the mechanism behind the \nbeneficial role of resveratrol through lncRNAs is still \nelusive. Nevertheless, resveratrol has the therapeutic \npotential to treat endometriosis. This is proved by a \nfinding where resveratrol could significantly decrease \ncell viability (P  = 0.0065 to P  = 0.0180) and cell migra -\ntion (P  < 0.001 to P = 0.0225) in endometriosis. Res -\nveratrol could significantly increase the number of \napoptotic cells (P  = 0.0031 to P  = 0.0432) in endome -\ntriotic cell lines [202]. Contextually, Xiaoji decoction \nprepared from “Psoralea corylifolia L., Coriolus ver -\nsicolor (L. ex Fr.) Quel., Astragalus membranaceus \n(Fisch.) Bge, Curcuma phaeocaulis Val., Buthus marten -\nsii Karsch, Scolopendra subspinipes mutilans L. Koch, \nRheum palmatum L., Hedyotis diffusa Willd” has been \nfound to significantly (P  < 0.05) decrease the expression \nof lncRNA HOTAIR [203] (Table 2 ).\nTable 2 (continued)\nTherapeutic target Phytoconstituents of therapeutic significance Reference\nCOX-2,  PGE2 and EP4 receptors Withaferin-A downregulates COX-2; Kaempferol significantly \nsuppresses the mRNA expression of COX-2; Granatin-B \nand Kaempferol significantly suppress the expression of  PGE2; \nXiaoji decoction prepared from “Psoralea corylifolia L., Coriolus \nversicolor (L. ex Fr.) Quel., Astragalus membranaceus (Fisch.) \nBge, Curcuma phaeocaulis Val., Buthus martensii Karsch, \nScolopendra subspinipes mutilans L. Koch, Rheum palma-\ntum L., Hedyotis diffusa Willd” significantly decreases mRNA \nand protein expression levels of EP4\n[203, 206, 219, 221]\nHGF, urokinase-type plasminogen activator Quercetin suppresses HGF signaling; resveratrol suppresses \nmRNA expression of urokinase plasminogen activator\n[224, 225]\nIGF-1 Apigenin inhibits IGF-1-induced activation of IGF-1R [226]\nFibrinogen alpha chain Curcumin lowers plasma fibrinogen [227]\nLeptin and its receptor Curcumin inhibits leptin expression and secretion; resveratrol \nreduces mRNA expression and secretion of leptin\n[228, 229]\n\nPage 14 of 27Paul et al. Middle East Fertility Society Journal            (2025) 30:6 \nPhytoconstituents targeting VEGF, CD31, Tie‑2, and Ang‑2 \nmRNA\nResveratrol can decrease the expression levels of VEGF \n(P = 0.0052 to P = 0.0243) and Ang-1 mRNA (P < 0.001 to \nP = 0.0382) [202]. Genistein has been found to decrease \nVEGF-induced activation of JNK and p38 but not ERK-\n1/2. This leads to a decreased angiogenesis [186]. Api -\ngenin strongly suppresses HIF-1α expression and its \ndownstream VEGF-A/VEGFR2 pathway [176]. Cell line \nstudies have shown that purified polysaccharides from \nthe fruit bodies of Lentinus edodes can downregulate \nthe expression of CD31 [204]. 5α-hydroxycostic acid and \nhydroxyisocostic acid (two eudesmane-type sesquiterpe -\nnes from the herb Laggera alata) can inhibit Tie-2 phos -\nphorylation. 5α-hydroxycostic acid and hydroxyisocostic \nacid can significantly (P < 0.005) suppress the expression \nlevel of Ang-2 mRNA [205] (Table 2).\nPhytoconstituents targeting cytokines and others\nWithaferin-A (a steroidal lactone) reduces the levels \nof IL-1β, IL-6, and TNF-α [206]. Similarly, quercetin \ndecreases mRNA and protein levels of IL-1β induced \nIL-6 in a dose-dependent manner [207]. Resveratrol sup -\npresses inflammation in endometriosis by suppressing \nTNF-α induced IL-8 release [208]. Quercetin (P < 0.0005) \nand tuberostemonine-O (P < 0.005) can significantly \ninhibit IL-2 production. Quercetin also significantly \n(P < 0.0005) reduces the mRNA and protein expression \nof IFN-γ [209]. Apigenin can significantly (P < 0.001) \ndecrease the expression of both IL-10 and TNF-α [210]. \nRosmarinic acid can suppress the production of IL-17A \n[211]. Curcumin can significantly (P < 0.0001) suppress \nIL-18 production [212]. Licochalcone-A suppresses IL-1β \nand IL-18 expression [213]. Apigenin and luteolin can \nsignificantly (P < 0.05) suppress the production of IL-33, \nbut apigenin was better than luteolin [214]. Quercetin \ncan significantly (P < 0.05) suppress the mRNA and pro -\ntein expression of MCP-1 [215] (Table 2).\nPhytoconstituents targeting NF‑kB/COX‑2 or Nrf2/Keap1/\nHO1 axis\nAndrographolide (a diterpenoid lactone) suppresses the \nrole of NF-kB by inhibiting its DNA-binding ability and \nsubsequent release of COX-2, tissue factor, and nerve \ngrowth factor. This will lead to a decrease in ectopic \nendometrial cell proliferation and a reduction in the size \nof ectopic lesions. Andrographolide has been found to \nreduce pain in the murine modal of endometriosis [216, \n217]. Curcumin also partly inhibits NF-kB [185]. Simi -\nlarly, withaferin-A downregulates COX-2/NF-kB sign -\naling and suppresses the proliferation of endometriotic \nlesions [206]. Murine model studies have proved that \nflavonoids (eriodictyol, glycitin, 5-O-methylgenistein, \n( +)-catechin 7-O-beta-D-xyloside, (-)−8-prenylnarin -\ngenin, and ( ±)-naringenin) from Phaleria macrocarpa \ncan suppress the growth of endometriosis lesions [218]. \nPrevious studies with quercetin have proved that it can \nsuppress MAPK and NF-kB signaling pathways [207] \nand consequent endometriotic lesions [182]. Naringenin \nprevents endometriotic lesions by modulating Nrf2/\nKeap1/HO1 axis. It decreases the expression levels of \nNrf2 and HO1 but increases the expression of Keap1 in \na dose-dependent manner [86]. Kaempferol significantly \n(P < 0.05) suppresses the mRNA expression of COX-2 \n[219]. Gambogenic acid has the potential to downregu -\nlate the expression of COX-2 mRNA [220] (Table 2).\nPhytoconstituents targeting  PGE2 and its receptors\nGranatin-B can significantly (P < 0.001) suppress the \nexpression of  PGE2 [221]. Kaempferol can also signifi -\ncantly (P < 0.05) suppress the production of  PGE2 [219]. \nXiaoji decoction prepared from “Psoralea corylifolia L., \nCoriolus versicolor (L. ex Fr.) Quel., Astragalus mem -\nbranaceus (Fisch.) Bge, Curcuma phaeocaulis Val., Buthus \nmartensii Karsch, Scolopendra subspinipes mutilans L. \nKoch, Rheum palmatum L., Hedyotis diffusa Willd” has \nbeen found to significantly (P < 0.05) decrease the mRNA \nand protein expression of EP4 [203] (Table 2).\nPhytoconstituents targeting MMPs\nKaempferol can significantly (P < 0.05) decrease MMP -1 \nand MMP-3 protein expression levels [219]. Curcumin \npretreatment (48 mg/kg body weight) plays a protective \nrole against endometriosis by inhibiting MMP-2 activity \n[222]. Similarly, withaferin-A is very effective in down -\nregulating the expression levels of MMP-2 and MMP-9. \nIt also suppresses their activities in ectopic endometrium \n[206]. Similarly, quercetin can suppress MMP-9 [207]. \nAs per a recent study, quercetin may suppress MMP-2, \nMMP-9, and other proteins to suppress the proliferation \nof EESC [223]. Naringenin can suppress both MMP-2 \nand MMP-9 and prevent invasion of endometrial cells \n[86]. Resveratrol reduces MMP-2 (P < 0.001 to P = 0.0180) \n[202]. Genistein inhibits VEGF augmented secretion and \nactivity of MMP-2 and MMP-9 [186] (Table 2).\nPhytoconstituents targeting HGF, urokinase‑type \nplasminogen activator, IGF‑1, fibrinogen alpha chain, \nleptin, and its receptor\nQuercetin can suppress HGF signaling by suppressing \nthe AKT pathway [224] and resveratrol can suppress \nmRNA expression of urokinase plasminogen activator \n[225]. Apigenin can inhibit IGF-1-induced activation \nof the IGF-1 receptor (IGF-1R) and subsequent signal -\ning [226]. Curcumin injection has been found to lower \nplasma fibrinogen concentration [227]. Curcumin can \n\nPage 15 of 27\nPaul et al. Middle East Fertility Society Journal            (2025) 30:6 \n \nalso inhibit the expression and secretion of leptin [228]. \nSimilarly, resveratrol can reduce the mRNA expression of \nleptin and its secretion [229] (Table 2).\nPlant extracts which can alleviate endometriosis\nExtracts of Achillea biebersteinii and Artemisia princeps \n(family Asteraceae), Euterpe oleracea (family Arecaceae), \nPrunella vulgaris (family Lamiaceae), Tripterygium wil -\nfordii (family Celastraceae), etc., may prevent endome -\ntriosis and improve the quality of life [181].\nEffects of phytoconstituents on different molecular \ntargets for the treatment of endometriosis are shown in \nTable 2 and Fig. 2.\nEffects of phytoconstituents on infertility\nApigenin can upregulate SIRT1. This will reduce oxida -\ntive stress and delay the aging of postovulatory oocytes \n[230]. Apigenin also protects and restores ovarian func -\ntion in murine models of polycystic ovary syndrome \n[231]. Genistein has a protective role in female mice \nfertility [232]. Resveratrol supplementation in human \nembryo culture medium can significantly improve \nembryo quality in older women over 40  years of age \n[233]. Anthocyanins can reduce the risk of gestational \ndiabetes mellitus (GDM) [234] which will be increased by \nendometriosis [32]. The murine model study has proved \nthat quercetin inhibits endothelin-1 and endothelin-1 \ntype A receptors and improves the quality of pregnancy \nby reducing hypertension resulting from reduced uterine \nperfusion [235]. Impaired uterine perfusion is strongly \nassociated with ovarian endometrioma [236] and infertil -\nity [237]. Naringenin has a renoprotective effect on GDM \n[238]. Kaempferol can oppose the effects of oocyte aging \non fertilization capacity [239]. Ursolic acid can moder -\nately reduce the risk of fetal development defects in GDM \n[240]. Curcumin can manage GDM and fetal growth \nrestriction [241], which are the pathological complica -\ntions of endometriosis [32, 242]. Intravenous ellagic acid \nhas increased the frequency of abortion in pregnant mice \n[243]. This raises concerns regarding pregnancy. Car -\nnosic acid regulates oxidative stress and improves early \nporcine embryonic development [244]. In  vitro study \nFig. 2 Therapeutic effects of different phytoconstituents\n\nPage 16 of 27Paul et al. Middle East Fertility Society Journal            (2025) 30:6 \nhas shown that luteolin can improve porcine embryonic \ndevelopment by counteracting oxidative stress [245].\nDiscussion\nThe success of endometriosis treatment is dependent on \nthe proper understanding of the pathogenesis. Though \nmuch has been understood, certain mechanisms are con -\ntroversial and elusive. There are contradictory findings \nabout the expression levels of progesterone receptors in \neutopic endometrium [59–61]. The significance of the \nabove information is further increased by the finding that \neutopic endometrium shows greater proliferation abil -\nity, implantation, and angiogenesis compared to ectopic \nendometrium. Interestingly, eutopic endometrium deter-\nmines the fate of the endometrial tissue, either to survive \nor to die outside the uterus and become ectopic endome -\ntrium. Eutopic endometrium may be the reason behind \ninfertility in endometriosis [147, 246]. It is noteworthy \nthat progesterone inhibits the activation of NK cells \n[247]. Progesterone particularly suppresses the immune \nresponse during pregnancy. Progesterone induces cas -\npase and destroys peripheral blood NK cells; this will \nfavor pregnancy [248]. Notably the level of progesterone \nshows a progressive increase from the first trimester to \nthe third trimester [65]. Decreased peripheral NK cell \ncytotoxicity is associated with endometriosis [249]. NK \ncells prevent the development of ectopic endometriotic \ntissue in the peritoneal cavity [125]. Progesterone also \nincreases the number of NK cells, and the induction of \nNK cells in the endometrium is progesterone-dependent. \nThe count of NK cells increases even when pregnancy \nensues and NK cells are described to have a protective \nrole during pregnancy. The secretory phase of the men -\nstrual cycle (non-pregnant) shows an increased proges -\nterone level and an increased number of NK cells [250]. \nThis shows the complex effect of progesterone on the NK \ncell population. This may raise concern about the practi -\ncal implications of progesterone therapy in patients with \neutopic endometrium with differential expression levels \nof progesterone receptors. This finding shows a scope for \nfuture research to overcome the ambiguity and have bet -\nter therapeutic outcomes.\nThe apparent negative role of progesterone receptor A \nin endometriosis, as well as in pregnancy among endo -\nmetriosis patients [62, 63, 65, 66], raises demand for the \nidentification of novel phytoconstituents as progesterone \nreceptor A antagonists. Many plant extracts have been \nfound to have an antiprogesterone effect. These include \n“Cortex eucommiae, Folium artemisiae argyi, Glycyr -\nrhiza uralensis, Euscaphis japonica, Ailanthus altissima, \nDioscorea opposite, Angelica sinensis, Atractylodes mac -\nrocephala koidz and Scutellaria baicalensis” [251]. Nev -\nertheless, no single phytoconstituent has been identified \nand isolated as a selective progesterone receptor A antag-\nonist. Identification of active phytoconstituents from \nthese plants and proving their selectivity as progesterone \nreceptor A antagonists may improve the treatment strat -\negy for endometriosis. Similarly, the impact of apigenin \non miR-194-3P was not established. As miR-194-3P is \nresponsible for progesterone resistance [119] and api -\ngenin can modulate progesterone receptor [175], hence, \nfuture research unveiling the effect of apigenin on miR-\n194-3P will explain its mechanistic pathway in a better \nway.\nFindings with respect to the expression levels of IL-18 \nin endometriosis are controversial. There are many con -\ntradictory evidences [156, 157]. The correlation between \nIL-37 and TNF-α is also controversial. As per one study, \nIL-37 suppresses TNF-α [163], whereas, the other study \nshows a positive correlation between IL-37 and TNF-α \nlevels [164]. Thus, treatment modalities targeting IL-37 \nmay have dichotomous outcomes. Similarly, the role of \nIL-12 in the context of endometriosis is elusive. It can \nincrease the production of IFN-γ in NK cells [123] and \nNK cells secrete IFN-γ and TNF-α [252]. The role of \nIFN-γ and TNF-α in COX-2 induction, proliferation \nof endometrial cells, angiogenesis, invasion, pain, and \ninfertility is well established [121, 122, 165]. Strangely, \nIL-12 inhibits peritoneal endometriosis via activation of \nNK cells [125]. Thus, targeting IL-12 or NK cells to treat \nendometriosis may have unexpected outcomes unless \nfurther clarity is obtained regarding their actual roles in \nendometriosis. The speculation on unexpected therapeu-\ntic outcomes following NK cell targeting is also corrobo -\nrated by a very recent study [253]. Thus, future research \nto untangle the complex relationship will help to achieve \nbetter therapeutic outcomes.\nThe role of genetic mutation in endometriosis is subject \nto ethnic variation as can be seen with respect to WNT4  \nrs16826658 [99–101]. Thus, the effects of every genetic \nmutation in the context of endometriosis should be \ndeeply studied among the worldwide population to iden -\ntify the susceptible ethnic group. This will help to initiate \nthe therapy at an early age and maximize the therapeutic \noutcome.\nHigher expression of Ang-2 mRNA in eutopic endome-\ntrium seems to favor angiogenesis [147] but other study \nfinds that Ang-2 protein has an inhibitory effect on angi -\nogenesis [148]. Interestingly, Ang-2 favors the sprouting \nof blood vessels in conjugation with VEGF. Ang-2 favors \nthe production of MMPs leading to endometriosis [254]. \nThe role of Ang-2 in neovascularization and pathologi -\ncal progression of endometriosis is largely dependent \non VEGF and MMPs. Therefore, phytoconstituents may \nsuppress its pathological impact by targeting VEGF and \nMMPs. This above controversy opens the door for future \n\nPage 17 of 27\nPaul et al. Middle East Fertility Society Journal            (2025) 30:6 \n \nresearch where the downregulating effect of any phyto -\nconstituent on VEGF and its subsequent effect on Ang-\n2-induced angiogenesis can be studied.\nThe actual role of quercetin on p38MAPK is compli -\ncated because one study reports that quercetin can sup -\npress p38MAPK [182] whereas, another study reports \nthat it has no effect on the p38MAPK pathway [224]. This \ndemands further research on the existence and role of \nconfounding variables.\nThere are chances of many future researches with phy -\ntoconstituents because many of them were not tested for \ntheir potential to suppress the expression of miRNAs to \ntreat endometriosis. Similarly, COX-2 inhibitory phyto -\nconstituents such as farnesiferol A, piperine, cedrelanol, \nusnic acid [255], and gambogenic acid [220] should be \ntested to unveil their hidden potential to treat endome -\ntriosis. Similarly, the identification of newer phytocon -\nstituents that can target IL-15, IL-16, IL-27, and IL-37 \nmay have positive outcomes on the treatment of endo -\nmetriosis. The scope of research further increases as very \nlittle data are available on the direct effect of shogaol, \ndemethoxycurcumin, capsaicin, withaferin-A, 6‐paradol, \ntuberostemonine-O, rosmarinic acid, and licochalcone-A \non pregnancy. In this regard, it is worth mentioning that \nthe negative effect of ellagic acid in pregnant mice [243] \nmay be ignored and outweighed by its protective role in \nendometriosis and by the combined effects of other preg-\nnancy-favoring phytoconstituents. This prediction opens \na narrow room for research where ellagic acid can be \ntried against the combined potency of other pregnancy-\nfavoring phytoconstituents.\nPotential toxicity and safety concerns of these phy -\ntoconstituents have been addressed on the basis of the \nfollowing reports. Data from animal and human studies \nshow that apigenin is quite safe at high doses and no tox -\nicity has been reported [256, 257]. Similarly, a mixture of \ngenistein, daidzein, and glycitein has shown minimal tox-\nicity in post postmenopausal women at a very high dose \n(16  mg/kg body wight) [258]. The murine model study \nhas proved that genistein did not show mutagenic or clas-\ntogenic effects; this gave the answer to a concern raised \non its mutagenic or clastogenic properties [259]. Resvera-\ntrol has shown an excellent safety profile at 1 gm dosing \nin a short-term course, adverse effects may arise in non-\nalcoholic fatty liver disease at a dose of 2.5 g or more/day. \nAdverse effects include nausea, vomiting diarrhea, and \nliver dysfunction [260]. Other studies also found resvera -\ntrol to be safe for human consumption [261]. No much \ndata could be retrieved for 5α-hydroxycostic acid and \nhydroxyisocostic acid. However, in non-toxic doses, they \nwere able to suppress human umbilical vein endothelial \ncell proliferation induced by VEGF and vessel formation \nin zebrafish embryos [205]. Anthocyanins obtained from \ngrape skin extract have been declared safe at 2.5  mg/\nkg by the Joint FAO/WHO Expert Committee on Food \nAdditives. Animal studies have also shown a wide mar -\ngin of safety [262]. Clinical trials have shown the benefi -\ncial effects of quercetin and found it safe for human use \n[263]. In general, oral intake of quercetin is considered \nsafe in humans [264]. Naringenin has been found safe \nin humans at an oral dose range of 150 to 900 mg [265]. \nPreclinical and clinical studies have shown low toxicity \nand a wide margin of safety for kaempferol [266]. The \nmurine model study has shown that withaferin-A is safe \nat 2000  mg/kg [267]. Preclinical studies and clinical tri -\nals show that ursolic acid in nanoparticle form can have \nbetter therapeutic effects without any serious adverse \neffects [268]. Shogaol has been found to be a novel phy -\ntoconstituent; it shows no toxicity to normal cells at a \ndose that is lethal for cancer cells [269]. Phase 1 clinical \ntrial has shown that 8000 mg of curcumin for 3 months \ndid not produce any toxicity [270]. Curcuma extract has \nalso been enrolled in clinical trials to determine its effi -\ncacy in alleviating endometriosis-associated pain (Clini -\ncalTrials.gov ID NCT04150406). Similarly, the safety \nprofile of demethoxycurcumin is understood from the \nfact that there are many commercial preparations avail -\nable that contain curcumin, demethoxycurcumin, and \nbisdemethoxycurcumin in the ratio of 66:23:11. Dem -\nethoxycurcumin is used in the food industry and is also \na folk medicine and found to have a neuroprotective role \n[271]. Capsaicin powder taken by oral route was well tol -\nerated by patients suffering from unexplained chronic \ncough and airway symptoms [272]. Ellagic acid has been \nkept under the “generally recognized as safe” category \nby USFDA for human consumption [273]. 6-paradol has \nbeen enrolled in clinical trials and found to be effec -\ntive without any adverse effects [274]. Patients treated \nwith 6-gingerol did not show any toxicity during a phase \nII randomized double-blind placebo-controlled study \n[275]. There is no data available on the safety profile of \noral/parenteral formulation of carnosic acid but pre -\nclinical study shows a minimal toxicity of carnosic acid. \nThe LD50 value as per the acute oral toxicity study is \n7100 mg/kg in mice [276]. The safety profile of carnosic \nacid and rosmarinic acid can be understood from the \nenrolment of rosemary extract in phase 2 clinical trials \nfor the management of periodontitis (ClinicalTrials.gov \nID NCT06601608). Similarly, rosemarinic acid has been \nincorporated as a dietary supplement to battle fatigue in \ncancer patients and it was under phase 3 trial (Clinical -\nTrials.gov ID NCT04546607). The availability of data on \ntuberostemonine-O toxicity in humans is less, but ani -\nmal studies show that tuberostemonine can be given by \nboth oral and intraperitoneal routes in guineapigs, but \nthe efficiency is better when given by intraperitoneal \n\nPage 18 of 27Paul et al. Middle East Fertility Society Journal            (2025) 30:6 \nroute [277]. Similarly, luteolin nanoethosomes is effec -\ntive by the oral route; such formulation has addressed the \nissues with low oral bioavailability of luteolin [278]. No \ndata related to the safety profile of luteolin on humans \ncould be retrieved. The safety of luteolin can only be pre -\ndicted from its enrollment in numerous clinical trials \nwith different pathological conditions (ClinicalTrials.gov \nID NCT06047899, ClinicalTrials.gov ID NCT05204407). \nThe results of these trials have not been published yet. \nSimilarly, no data could be retrieved related to the safety \nof granatin-B on humans but there are certain preclinical \nstudies. There are three clinical trials that are reported \nto date with licochalcone-A. The trials were conducted \nin the context of human oral squamous cell carcinoma \nand acne. One of the trials represents phase 3 enrollment \n(ClinicalTrials.gov ID NCT03292822, ClinicalTrials.gov \nID NCT04002024, ClinicalTrials.gov ID NCT02173054). \nThere is a scarcity of safety data for some phytoconstit -\nuents in humans; because very little research has taken \nplace with these phytoconstituents. This shows a broad \nscope of research in the future.\nThe future direction of research will be towards the \ngeneration of safety, compatibility data, and the deter -\nmination of the synergistic potential of these phytocon -\nstituents using Caenorhabditis elegans [279]. This will be \nfollowed by the determination of the combined safety/\ntoxicity of these phytoconstituents and the determination \nof therapeutic efficacy in cell lines and animals.\nThe limitations of translating these findings into human \ntherapy are increased by the scarcity of clinical data in \nthis context. Hence, it will be a challenging task due to \nthe novelty of the study. Nevertheless, these limitations \nopen newer avenues for many research.\nTo envisage the scope of phytoconstituents in the con -\ntext of emerging concepts of endometriosis therapy, it \nis necessary to understand the mechanism of action of \nemerging therapies/concepts. Some emerging strate -\ngies/concepts to treat endometriosis include photody -\nnamic therapy (PDT), hyperthermia treatment (HTT), \ngene therapy, immunotherapy, stem cell treatment, etc. \nThe principle of PDT therapy depends on the production \nof ROS, photo-oxidation of target cells, and their death. \nHTT increases the vulnerability of cancer cells to chemo \nand radiation therapy by inhibiting DNA repair enzymes. \nGene therapy for endometriosis is expected to make a dif-\nference in the management of endometriosis. However, \nthe gene therapy of endometriosis is not yet practiced \nrather can be seen in the preclinical studies. Gene therapy \ntargets endometriotic lessions and VEGF-A gene activity. \nGene therapy also employs miRNAs, whereas immune \ntherapy depends on the recruitment of macrophages to \nectopic lesions and macrophage-mediated engulfment of \nabnormal endometrial cells. Stem cell therapy employed \nin mice has shown promising results and has been found \nto have anti-inflammatory effects [280]. It has been found \nthat quercetin generates ROS and induces apoptosis of \nendometriotic cells. Quercetin also reduces the size of \nendometriotic lesions. Quercetin also induces DNA frag -\nmentation [182]. Thus, quercetin can mimic the mecha -\nnism of action of PDT and HTT. Apigenin suppresses the \nVEGF-A/VEGFR2 pathway [176]. Apigenin possesses an \nanti-inflammatory effect [177]. Similarly, Withaferin-A \nreduces the levels of IL-1β, IL-6, and TNF-α. This shows \ntheir anti-inflammatory potential [206]. Curcumin and \ngenistein modulate the expression levels of many miR -\nNAs [189–191]. Thus, apigenin, withaferin-A, curcumin, \nand genistein show mechanisms of action similar to gene \ntherapy and stem cell therapy.\nThe above findings make us hypothesize that the pro -\nposed formulation may establish itself as a stand-alone \ntherapy. However, preclinical evaluation will predict the \npossibility based on the therapeutic outcome. Presently \nwe have not come across any research that reflects the \ncontraindication for these phytoconstituents in endo -\nmetriosis. This enhances the possibility of being a stand-\nalone therapy. Even, adverse effects are very scarce which \nare reported above. However, clinical studies in postmen-\nopausal women have shown that genistein may produce \ngastrointestinal side effects [281]. Similarly, resveratrol \nis associated with ROS-mediated proteolysis and DNA \ndamage [282]. However, this seems to be an advantage \nas PDT therapy of endometriosis depends on the pro -\nduction of ROS [280]. Thus, actual adverse effects of the \nformulation have to be determined to evaluate the safety \nprofile.\nPrima facie the therapeutic implications may include \nthe following: a decrease in the proliferation of EESC, \ninvasion, vascularization, pain sensation, inflammation, \ngestational diabetes mellitus, and fetal growth restriction. \nThere may be an increase in the fertility rate.\nConclusion\nSeveral phytoconstituents have been found to effec -\ntively target the molecular mediators of endometriosis. \nHerbal formulations containing phytoconstituents such \nas apigenin, genistein, resveratrol, 5α-hydroxycostic \nacid, hydroxyisocostic acid, anthocyanins, quercetin, \nnaringenin, kaempferol, withaferin-A, ursolic acid, \nshogaol, curcumin, demethoxycurcumin, capsaicin, \nellagic acid, 6‐ paradol, 6‐ gingerol, carnosic acid, tuber -\nostemonine-O, rosmarinic acid, luteolin, granatin-B, \nand licochalcone-A may be useful in the treatment of \nemdometriosis. This formulation may decrease the pro -\nliferation of EESCs, their invasion, vascularization, pain \nsensation, inflammation, gestational diabetes mellitus, \n\nPage 19 of 27\nPaul et al. Middle East Fertility Society Journal            (2025) 30:6 \n \nand fetal growth restriction. There may be an increase \nin the fertility rate also. This is due to their ability to \nregulate the expression of many molecular targets such \nas VEGF-A/VEGFR2 pathway, p38MAPK/ERK-1/2/\nPI3K/protein kinase B (AKT), HIF-1α, IL-1β, IL-2, IL-6, \nIL-8, IL-10, IL-17A, IL-18, IL-33, TNF-α, NF-kB, IFN-\nγ, IGF-1-induced activation of IGF-1R, ER-α and ER-β \nreceptors, miR-95, miR-103, miRNA-138, miRNA-155, \nmiR-183, miR-223, MMP-1, MMP-2, MMP-3, MMP-\n9, lncRNA-MEG3, lncRNA-H19, Ang-1 mRNA, Ang-2 \nmRNA, mRNA of urokinase plasminogen activator, \nmRNA expression and secretion of leptin, CD31, Tie-\n2, MCP-1 mRNA and protein, HGF, Nrf2, HO1, Keap1, \nCOX-2, PGE-2, MKNK1, and human DNA TOP3A. \nHowever, further clinical validation is required to \ndetermine the safety, compatibility, and therapeutic \nefficacy of this formulation.\nAbbreviations\nvWF  Von Willebrand factor\nADAMTS13  A disintegrin and metalloproteinase with thrombospondin \nmotifs 13\nCOMT  Catechol-O-methyltransferase\nCOPD  Chronic obstructive pulmonary disease\nAD  Alzheimer’s disease\nHPV  Human papillomavirus\nPOD  Pouch of Douglas\nrASRM  Revised American Society for Reproductive Medicine\nEFI  Endometriosis fertility index\nART   Assisted reproductive technology\nER-α  Estrogen receptor-alpha\nER-β  Estrogen receptor-beta\nIL-1  Interleukin-1\nCOX  Cyclooxygenase\nPGE2  Prostaglandin-E2\nSNP  Single nucleotide polymorphism\nVEGF  Vascular endothelial growth factor\nCD31  Cluster of differentiation 31\nTie2  TEK tyrosine kinase\nWISP-3  WNT-inducible signaling pathway protein-3\nMAPK  Mitogen-activated protein kinase\nHIF-1α  Hypoxia-inducible factor 1-alpha\nERK  Extracellular signal-regulated kinase\nNF-kB  Nuclear factor kappa B\nMMP-9  Metalloproteinase-9\nGSTM1  Glutathione S-transferase mu 1\nMKNK1  MAP kinase-interacting serine/threonine-protein kinase 1\nTOP3A  DNA topoisomerase III alpha\nEESC  Ectopic endometrial stromal cells\nlncRNA  Long non-coding RNA\nMEG3  Maternally expressed gene 3\nmiRNA  MicroRNA\nAcknowledgements\nNone.\nAuthors’ contributions\nD.P ., R.A. and M.A.I wrote the main manuscript text and D.P . prepared Figs. 1–2. \nAll authors reviewed the manuscript.\nFunding\nThis work did not receive any funding.\nData availability\nNo datasets were generated or analysed during the current study.\nDeclarations\nEthics approval and consent to participate\nNot applicable.\nConsent for publication\nNot applicable.\nCompeting interests\nThe authors declare no competing interests.\nReceived: 26 September 2024   Accepted: 15 March 2025\nReferences\n 1. 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