An overview of endometriosis and molecular target-based therapeutic approach

Background Endometriosis has become a global concern. Fifty percent of the affected women become infertile. Ten percent of the female population, which represents women in their reproductive age and girls, is affected globally. It shows a strong correlation with thyroid, endometrial, and breast cancer. It disrupts the psychological, social, and eco- nomic wellbeing and sexual life of women. Main body Modern hormonal therapy relies upon estrogen–progestin combinations. Other drugs include pro- gestins, gonadotropin-releasing hormone agonists and antagonists. Some patients remain non-responsive to these therapies, and others show adverse effects such as intolerance, weight gain, acne, and seborrhea. Similarly, surgery has its own complications which include late bowel, ureteral perforations, recto-vaginal, and uretero-vaginal fistulas. Neither modern therapeutic nor surgical approaches could alleviate endometriosis. Besides, the cost of treatment is overburdening. This necessitates the designing of an alternative therapeutic approach which could alleviate endo- metriosis. This has led to the identification of molecular targets and the exploration of different phytoconstituents that could modulate these targets.

Formulation containing different phytoconstituents such as apigenin, genistein, resveratrol, 5α-hydroxycostic acid, hydroxyisocostic acid, anthocyanins, quercetin, naringenin, kaempferol, withaferin-A, ursolic acid, shogaol, curcumin, demethoxycurcumin, capsaicin, ellagic acid, 6‐paradol, 6‐gingerol, carnosic acid, tuberoste- monine-O, rosmarinic acid, luteolin, granatin-B, and licochalcone-A may be useful in the treatment of emdometriosis. This formulation may decrease the proliferation of ectopic endometrial stromal cells, their invasion, vascularization, pain sensation, inflammation, gestational diabetes mellitus, and fetal growth restriction. There may be an increase in the fertility rate also. This is due to its ability to regulate the expression of many molecular targets such as VEGF- A/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, IL-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, miRNA-155, miR-183, miR-223, MMP-1, MMP-2, MMP-3, MMP-9, lncRNA-MEG3, lncRNA-H19, Ang-1 mRNA, Ang-2 mRNA, mRNA of urokinase plasminogen activator, mRNA expression and secretion of leptin, CD31, Tie-2, MCP-1 mRNA and protein, HGF, Nrf2, HO1, Keap1, COX-2, PGE-2, MKNK1, and human DNA TOP3A. However, further research is required to determine the safety, compatibility, and therapeutic efficacy of this formulation.

Endometriosis, Estrogen, Progesterone, Inflammation, Pathogenesis, Plant products

Endometriosis is a chronic inflammatory disorder of the uterus triggered by excessive production of estrogen by the ovaries [1, 2]. Patients experience severe chronic pel - vic pain due to the growth of endometrial tissue outside the uterus [3, 4]. Other types of pain include dysmenor - rhea, dyspareunia, dyschezia, and dysuria [5]. The biggest *Correspondence: Deepraj Paul [email protected] 1 Department of Pharmacology, College of Pharmacy, JSS University, Uttar Pradesh, Noida 201301, India 2 Department of Pharmaceutical Chemistry, Yenepoya Pharmacy College and Research Centre, Yenepoya (Deemed to Be University), Mangalore 75018, India Page 2 of 27Paul et al. Middle East Fertility Society Journal (2025) 30:6 concern with endometriosis is that 50% of the affected population becomes infertile. It is estimated that 10% of the female population, representing women in their reproductive age and girls, is affected globally [6]. The graveness of the disorder can be measured by its strong correlation with thyroid, endometrial, and breast can - cer [7, 8]. It disrupts the psychological, social, and eco - nomic wellbeing and sexual life of women [5]. Anxiety and depression are the most common observations in endometriosis [4]. To date, there is no cure available for endometriosis [9]. Pharmacological intervention for symptomatic endometriosis through hormonal therapy depends on estrogen-progestin combinations. Other drugs include progestins, gonadotropin-releasing hor - mone agonists and antagonists. Some patients remain non-responsive to these therapies and others show adverse effects such as intolerance, weight gain, acne, and seborrhea [10]. Similarly, surgical intervention has its own complications which include late bowel, ureteral perforations, recto-vaginal, and uretero-vaginal fistulas [11]. The recurrence rate of endometriosis after 2  years of conservative surgery was found in the range of 9.2– 29.4%, whereas the recurrence rate after a follow-up for 12 years was found to be 56.4% [12]. Neither therapeutic nor surgical approach could alleviate the disorder; even postoperative medical treatment could not prove its ben - efit [13]. Besides, the cost of treatment is overburdening [14]. Most importantly, medical treatment after surgi - cal intervention can only delay the recurrence of endo - metriosis but cannot completely cure the disorder [15]. Hence, it is crucial to understand the risk factors, com - plications, pathological correlations, and pathogenesis of endometriosis for a better therapeutic approach. Inter - estingly, many plant extracts have been found to sup - press the pathological parameters of endometriosis [16]. This makes it inevitable to revisit the disorder to identify potential therapeutic targets and explore the potential of purified phytoconstituents to modulate these targets. This review will try to propose a formulation containing a mixture of different phytoconstituents. This formulation is expected to alleviate endometriosis and improve the chances of pregnancy. Main text Risk factors Ladies presenting menstrual cycles with a greater num - ber of bleeding days are at higher risk of endometriosis [17]. First menstrual cycle occurring before the age of 11, shorter menstrual cycle (less than 27  days), obe - sity, Caucasian race, age between 25 and 29, daily alco - hol consumption (10  g per day), red meat consumption (more than 2 servings per day), smoking, etc., are some of the risk factors for endometriosis [18]. Exposure to certain chemicals such as polychlorinated biphenyls [19], arsenic, cadmium, lead, and mercury [20] can induce endometriosis. First-degree relatives are at higher risk of developing endometriosis [17]. Women in Rh-nega - tive blood group show two times higher susceptibility to develop endometriosis compared to the control group but the ABO system of blood grouping did not show any significant susceptibility compared to the control group. Involvement of genetic components is suspected [21]. A recent study has proved a strong genetic basis for endo - metriosis. Forty-two genome-wide significant loci have been identified for endometriosis. Thirty-one of these genes have been reported for the very first time [22]. Certain coagulation factor such as von Willebrand fac - tor (vWF) shows a positive causal association with endo - metriosis of the pelvic peritoneum and ovary. This may be related to a decreased plasma level of ADAMTS13 (A disintegrin and metalloproteinase with thrombospon - din motifs 13), which is required for cleaving vWF and maintaining its plasma level [23]. Some enzymes may increase the susceptibility to endometriosis. A slow acet - ylation phenotype of the enzyme N-acetyltransferase 2 is associated with a 130% increased risk of endometriosis [24]. Similarly, catechol-O-methyltransferase (COMT) 158G/A polymorphism may increase the susceptibility to endometriosis and adenomyosis [25]. Respiratory ail - ments can increase the susceptibility to endometriosis in a particular age group. Chronic obstructive pulmo - nary disease (COPD) in 40–60 years of women increases the susceptibility to endometriosis compared to women without COPD [26]. Hypovitaminosis D has been identi - fied as a potential risk factor for endometriosis [27]. Complications Endometriosis increases the chance for irritable bowel syndrome by more than two folds compared to women without endometriosis [28]. Endometriosis accompanied by adenomyosis is responsible for a significantly lower live birth rate than endometriosis alone [29]. First-time mothers with endo - metriosis generally represent abnormally located pla - centa, are more prone to have a premature baby, and undergo cesarean delivery [30, 31]. Endometriosis signifi- cantly increases the risk of gestational diabetes in natu - ral pregnancies but has no effect on conception through assisted reproductive technologies [32]. Endometriosis increases the chance of preeclampsia in women who con- ceive spontaneously [33]. Endometriosis significantly increases the risk of ischemic heart disease and cerebrovascular disease [34]. Cerebrovascular disease is again a risk factor for Alzhei - mer’s disease (AD). People with cerebrovascular disease show a significant increase in “formin-like protein 2, ” Page 3 of 27 Paul et al. Middle East Fertility Society Journal (2025) 30:6 which is responsible for amyloid and phosphorylated tau deposition and progression of AD [35]. Endometriosis favors a higher rate of high-risk human papillomavirus (HPV) infection [36]. A subsequent study has confirmed the presence of high-risk HPV infection in 60% of endometriosis patients. High-risk HPV infec - tion in the upper genital tract is associated with infertil - ity [37]. A newer study has also correlated HPV infection with pain and infertility in endometriosis patients [38]. The concern arises from the fact that the presence of high-risk HPV (predominantly type 16 and 18 HPV) shows the most frequent association with cervical cancer [39]. Pathological correlation Women with both anterior and posterior adenomyosis had shown higher co-existence of ovarian endometriosis and pelvic adhesion, whereas women with only posterior adenomyosis had shown heavy menstrual bleeding and oviduct obstruction. Women with anterior adenomyo - sis had shown a higher incidence of leiomyoma [40]. All these pathologies and endometriosis are interlinked. The prevalence of adenomyosis in endometriosis was 91.1%, whereas the prevalence of endometriosis in adenomyo - sis was 80.6% [41]. Similarly, endometriosis is described as the most common reason behind pelvic adhesion; 37.6% of pelvic adhesions result from endometriosis [42]. Studies have shown that other than endometrium, tubal mucosa also plays a role in endometriosis; endometriotic lesions so produced can in turn lead to tubal dysfunction [43]. In reality, endometrial tissue can be implanted any - where, but the preferred places are the ovary and pel - vic peritoneum [44]. A study has proved the correlation between adenomyosis and deep endometriosis, specifi - cally rectosigmoid endometriosis [45]; it is noteworthy that deep endometriosis can infiltrate into uterosacral ligaments, rectovaginal space, gastrointestinal tract, uri - nary tract, and rectosigmoid region. Involvement of the rectosigmoid region was observed in almost 90% of the cases with endometriosis [46]. Endometriosis can cause complete rectosigmoid obstruction [44]. Similarly, another study has shown the correlation between leio - myoma, adenomyosis, and endometriosis. One hundred eighty-one out of 208 leiomyoma patients had endome - triosis, and 9 out of the remaining 27 had adenomyosis as well as leiomyoma. Only 18 patients were affected with leiomyoma alone [47]. Endometriosis and eleven pain-conditions have shown a significant genetic correlation. Such pains also include migraine, back pain, and multisite chronic pain. Certain inflammatory conditions such as asthma and osteoarthritis show a significant genetic correlation with endometriosis [22]. Classification/grading/scoring of endometriosis Ultrasound-based endometriosis staging system and transvaginal ultrasound have classified the disorder into three stages. Stage I represents normal mobility of the ovaries, absence of non-bowel and bowel deep infiltrating endometriosis, normal “Pouch of Douglas”(POD), and the presence or absence of site-specific tenderness. This stage is identified as “mild stage disease” by the surgical complexity-based grading system, also categorized as level 1. Stage II represents endometrioma, with or with - out immobile ovaries, with or without non-bowel deep infiltrating endometriosis. However, POD remains nor - mal. This is identified as “moderate stage disease” by the surgical complexity-based grading system, also catego - rized as level 2. Stage III represents bowel deep infiltrat - ing endometriosis, the presence or absence of immobile endometrioma, and the presence or absence of POD. This is identified as a “higher stage disease” by the surgi - cal complexity-based grading system, also categorized as level 3 [48]. The revised American Society for Reproductive Medi - cine (rASRM) considers endometriosis of the peritoneum and ovary, obliteration of POD, and adhesions of the ovary and fallopian tube for the purpose of grading endo- metriosis. rASRM classifies endometriosis into 4 stages. Stage 1 is graded as “minimal” and has a score range of 1 to 5; stage 2 is graded as “mild” and has a score range of 6–15; stage 3 is graded as “moderate” and has a score range of 16–40; stage 4 is graded as “severe” and assigned a score more than 40. The points are allotted based on the size of the lesions and the nature of the lesions such as superficial or deep. In case of endometriosis of ova - ries, if a lesion on the ovary is less than 1 cm in size and superficial in nature, then the score allotted is 1. If the size of the superficial lesion is between 1 and 3 cm, then the score allotted is 2. If the size of the superficial lesion is more than 3 cm, then the score allotted is 4. In case of a deep endometriosis if the size is less than 1  cm, then the score allotted is 4. If the size is between 1 and 3 cm, then the score allotted is 16. If the size is more than 3 cm, then the score allotted is 20. Similarly, if obliteration of the POD (also known as posterior cul-de-sac) alone is considered and if it is found to be partial then a score of 4 is assigned, which falls under stage 1. Complete oblitera - tion receives a score card of 40, which represents stage 3 endometriosis. Similarly, scores are allotted for adhesions observed on the ovary and other places to indicate the stage of endometriosis. During the scoring of endometri - osis associated with the fallopian tube, higher scores are assigned if the end of the tube is found completely closed Page 4 of 27Paul et al. Middle East Fertility Society Journal (2025) 30:6 [49–52]. This kind of scoring system helps to decide the future course of therapy. Despite its wide acceptance, the rASRM system faces criticism for its failure to completely describe deep endo - metriosis. Later, the Enzian classification came into the picture which relies upon three compartments (com - partments A, B, and C) to grade endometriosis. Com - partment A considers the vagina and rectovaginal space; scores are allotted based on the size of the lesions. If the size of the lesion is less than 1 cm, then it receives a score of A1. If the size of the lesion is between 1 and 3 cm, then it receives a score of A2. If the size of the lesion is more than 3 cm, then it receives a score of A3. Compartment B considers lesions on the uterosacral ligament (USL), cardinal ligaments, and pelvic sidewall. Here, different grades such as B1, B2, and B3 are assigned based on the size of the lesions. The measurement considered for grad- ing the lesions remains the same as it was for compart - ment A; however, different alphabets are used for grading purposes. Compartment C considers rectal aspects—any lesion on the anterior wall of the rectum which is located up to 16 cm from the anal verge. Endometriosis involv - ing other organs of the pelvic cavity and distant organs is marked as “FA” indicating adenomyosis, “FB” indicat - ing involvement of the bladder, “FU” indicating intrinsic ureter involvement, “FO” indicating involvement of other locations, and “FI” as intestinal involvement. Any lesion located above 16  cm from the anal verge is classified under FI, and the grading size range remains the same as it was for A1 and B1. The grades assigned here are C1, C2, and C3. Other than this, many features are consid - ered under this grading system. Irrespective of several features, this system was criticized for not considering peritoneal or ovarian disease or adhesions. This led to the evolution of another system of classification called map - ping [18, 50, 52–54]. Mapping focuses on the distribution pattern of the endometriosis lesions; for this purpose, peritoneal com - partments are divided into 5 zones. Zone 1 represents the anterior compartment along with the anterior uterine serosa, round ligament, vesicouterine fold, and bladder. Zone 2 represents the lateral compartment along with the left and right ovary, ovarian fossa, tubes, mesosal - pinx, uterosacral ligaments, parametrium, and the ure - ter. Zone 3 represents the posterior compartment along with the posterior uterine serosa, the pouch of Douglas, the posterior vaginal fornix, and the bowel. Zone 4 rep - resents the abdominal wall. Zone 5 represents the dia - phragm. In case of unilateral endometrioma, zone 2 is the most affected part followed by zones 3, 1, 4, and 5 [55]. Ultrasound-guided mapping study is claimed to be very effective for preoperative planning and intraoperative management of deep infiltrating endometriosis [56]. Another type of classification system is known as the “endometriosis fertility index” (EFI). This is considered to be the first classification to predict the chances of fertil - ity in patients who have undergone surgical diagnosis and treatment of endometriosis [57]. This system considers structures like the fallopian tube, fimbria, and ovary and tries to identify associated injuries, abnormalities, and dysfunction. The fallopian tube will be considered under the “mild dysfunction” category if slight injury is present to the serosa of the tube. The term “moderate dysfunc - tion” is applicable if moderate limitation in mobility is observed, and the tube presents moderate injury to the serosa or muscularis. The term “severe dysfunction” is applicable when mobility is severely impaired and the presence of fibrosis of the tube or mild to moderate sal - pingitis isthmica nodosa is there. The term “non-func - tional” is used if complete obstruction of the tube and severe fibrosis/salpingitis isthmica nodosa are observed. While considering the fimbria, the term “mild dysfunc - tion” is used to indicate slight injury with minimal scar - ring. “Moderate dysfunction” represents moderate injury, scarring, and loss of fimbrial architecture and also rep - resents minimal intrafimbrial fibrosis. “Severe dysfunc - tion” indicates severe injury, scarring, and loss of fimbrial architecture but moderate intrafimbrial fibrosis. “Non- functional” fimbria indicates severe injury with exten - sive scarring and complete loss of fimbrial architecture. This stage also represents complete occlusion of the tube. While considering the ovary, the term “mild dysfunction” indicates the size of the ovary which is normal/nearly normal and mild injury to the ovarian serosa. “Moder - ate dysfunction” indicates moderate injury on the ovar - ian surface. The size of the ovary reduces to one-third or even more. “Severe dysfunction” indicates severe injury on the surface of the ovary. The size of the ovary reduces to two-third or even more. The term “non-functional” is applicable if the ovary is not present or encased in adhe - sions [58]. Scores are assigned based on the observation. These scores help to decide the course of treatment. If the EFI score is less than or equal to 4, then the recom - mendation is made for assisted reproductive technol - ogy (ART). If the EFI score is between 5 and 6, then it is recommended to go for non-ART management for 4 to 6 months followed by ART. If the EFI score is more than or equal to 7, then it is recommended to go for non-ART management for 6 to 9 months followed by ART [57]. Pathogenesis and therapeutic targets The pathogenesis of endometriosis revolves around four factors—genetic predisposition, progesterone resistance, estrogen dependence, and inflammation [59]. Among these, progesterone resistance theory involving eutopic endometrium of women with and without endometriosis Page 5 of 27 Paul et al. Middle East Fertility Society Journal (2025) 30:6 falls short of evidence and is somewhat ambiguous. Both normal and eutopic endometrium have shown incon - sistent patterns of expression of progesterone recep - tors. Ectopic endometrium has shown a decrease in the expression pattern of progesterone receptors [59, 60]. The level of progesterone receptor B in eutopic endome - trium was significantly lower in the endometriosis group compared to normal women. The expression level of pro- gesterone receptor B in eutopic endometrium has shown an inverse correlation with the degree of endometriosis [61]. Suppressed progesterone receptor expression is the reason behind “chronic pelvic pain, infertility, inflamma - tory disorders, and cancer. ” Both progesterone receptors A and B are required to facilitate pregnancy in healthy females. In fact, an optimum ratio of these receptors is required to maintain pregnancy [62]. It is worth mention- ing that progesterone receptor A has an inhibitory effect on the expression of progesterone receptor B. This leads to the negative regulation of the effects of progesterone receptor B and consequent hyperplasia of the endome - trium and inflammation [62]. It is noteworthy that the predominance of progesterone receptor B is responsible for progesterone signaling, whereas the predominance of progesterone receptor A decreases progesterone responsiveness [63]. A disrupted progesterone response is a hallmark event in endometriosis [64]. This raises con- cern about the role and expression level of progesterone receptor A in pregnancy among endometriosis patients because progesterone supports pregnancy. Normal preg - nancy shows a progressive increase in the levels of pro - gesterone from the first trimester to the third trimester. A low progesterone level at 6 to 8 weeks indicates an abnor- mal intrauterine pregnancy or an ectopic pregnancy [65]. The chance of pregnancy in endometriosis patients can be predicted from the finding that eutopic endome - trium expresses a significantly higher level of progester - one receptor A compared to normal women. Peritoneal endometriosis also shows the predominance of proges - terone receptor A. Interestingly, ovarian endometriosis also shows a significantly higher expression of proges - terone receptor A compared to peritoneal endometriosis [66]. This indicates a negative role of progesterone recep- tor A in pregnancy among endometriosis patients. This also implies the significance of progesterone resistance in endometriosis. A decreased expression and action of progesterone receptors is associated with such resistance [62], and oxidative stress plays a great role in progester - one resistance [67]. This is a real concern because oxida - tive stress and proinflammatory cytokines act in a cyclic manner where one stimulates the production of the other [68]. In this way, the vicious cycle of progesterone resist - ance and endometriosis will continue. Similar to proges - terone receptor A, the estrogen-alpha (ER-α) receptor has a pathological association with peritoneal and ovar - ian endometriosis [69]. It is also known to increase the chances of endometrial cancer, unlike the ER-β receptor, which has an opposing effect on ER-α function [69, 70]. ER-α is correlated with the severity of pain and any fail - ure to suppress ER-α expression by progestin therapy will lead to the recurrence of endometriosis after 1 year [71]. ER-β will have an alleviating effect on endometriosis but excess production of ER-β in stromal cells will have nega- tive effects. These include suppression of tumor necrosis factor-alpha (TNF-α)-mediated apoptosis and induced interleukin (IL)−1 production. Similarly, excessive ER-β receptors in the endothelial cells of the uterine micro - vasculature induce cyclooxygenase (COX) and prosta - glandin-E2 (PGE2) [72]. This indicates the therapeutic significance of the regulation of receptor expression. A genetic component has a strong association with endometriosis. Single nucleotide polymorphism (SNP) in a gene decides the role of the gene in a disease [73]. FSHB locus with SNP rs11031006 is associated with increased menstrual cycle length and decreased endometriosis risk [74], whereas FSHB/11p14.1 with SNP rs4071559 is asso- ciated with endometriosis as well as uterine leiomyomata [22, 73]. Different genes with SNP have been identified which increase the susceptibility to endometriosis. Some results were conflicting. However, a recent study has identified specific genes with their SNP to be the predisposing fac - tor. These include fibronectin 1 (FN1 rs1250248), wing - less-type mammalian mouse tumor virus integration site family member 4 (WNT4 rs7521902), growth regula - tion by estrogen in breast cancer 1 (GREB1 rs13394619), vezatin (VEZT rs10859871), and interleukin-1 alpha (IL1A rs6542095) [75]. Other SNPs of IL1A associated with endometriosis include rs6542095, rs11677416, rs3783550, rs3783525, rs3783553, rs2856836, rs1304037, and rs17561 [76]. These genes play their roles in dif - ferent pathways. FN1 rs1250248 is implicated in the angiogenic pathway, WNT4 rs7521902 in embryonic development, GREB1 rs13394619 in the hormonal path - way, VEZT rs10859871 in cytoskeleton regulation [75], and IL1A rs6542095 in various immune responses and inflammatory pathways [76]. FN1 rs1250248 increases the expression of angiogenesis-related proteins such as vascular endothelial growth factor (VEGF), cluster of dif - ferentiation 31 (CD31), TEK tyrosine kinase (Tie2), and Ve-cadherin through WNT-inducible signaling pathway protein-3 (WISP-3). FN1 rs1250248 elevates WISP-3 expression via focal adhesion kinase/mitogen-activated protein kinase/hypoxia-inducible factor 1-alpha (FAK/ MAPK/HIF-1α) axis. This axis is known to promote tumor angiogenesis [77]. FAK is known for its cancer- promoting role through extracellular signal-regulated Page 6 of 27Paul et al. Middle East Fertility Society Journal (2025) 30:6 kinase (ERK)−1/2 signaling [78]. ERK/MAPK pathway inhibits granulosa cell proliferation in endometrio - sis and affects the growth and development of oocytes [79]. MAPK pathway regulates the activation of nuclear factor kappa B (NF-kB) [80]. NF‐kB increases the tran - scription of HIF‐1α in response to many pathological conditions such as hypoxia and bacterial invasion [81]. NF-kB activation in macrophages and ectopic endo - metrial cells leads to the synthesis of proinflammatory cytokines, which leads to the formation of endometri - otic lesions [82]. NF-kB links chronic inflammation to cancer [83]. Similarly, HIF-1α can induce endometriotic lesions [84, 85]. This indicates that FN1 rs1250248 may initiate endometriotic lesions through FAK/ERK/MAPK/ NF-kB/HIF-1α/WISP-3 pathway. This shows a com - mon pathway between endometriotic lesions and cancer. Another pathway implicated in endometriotic lesions is the nuclear factor erythroid 2-related factor 2 (Nrf2)/ kelch-like ECH-associated protein 1(Keap1)/heme oxy - genase 1 (HO1) axis. The endometriotic lesion shows a significant increase in Nrf2 and HO-1 and a decrease in Keap1. Keap1 has a suppressing role on Nrf2 [86], and it is the key negative regulator of Nrf2 [87]. It is notewor - thy that endometriotic lesions show higher expression of VEGF, its receptor VEGFR-2, matrix metalloproteinase-9 (MMP-9), and activated macrophages (ED-1 positive cells). A positive correlation has been reported between VEGF and ED-1 expression [88]. Activated macrophages derived from the endometrium are responsible for the endometriotic lesions rather than macrophages derived from the peritoneal cavity [89]. Similar expression pat - tern of VEGF, VEGFR-2, and MMP-9 was observed in both endometriosis and cancer diseases including ovarian cancer [88, 90]. Previous studies have already proved the association between higher expression lev - els of MMP-9 and higher degree/stage of endometrio - sis [91]. This unveils the presence of a hidden ovarian cancer aggravating mechanism in the pathophysiologi - cal path of endometriosis [90]. Other MMPs which are crucial for the invasion of endometrial cells and vascu - larization in endometriosis include MMP-1, MMP-2 [92], and MMP-3 [93–95]. SNP of MMP3 276A allele is a risk factor for advanced endometriosis and infertility [95]. Another SNP that is associated with endometriosis in Greek women includes rs11556218 of the IL-16 gene [96]. Similarly, a different SNP rs4778889 of IL-16 is asso- ciated with endometriosis in Nigerian [97] and Chinese women [98]. This proves the role of ethnic variation in the involvement of different SNPs of the same gene in the pathogenesis of endometriosis. The five most significant gene polymorphisms asso - ciated with endometriosis include interferon gamma (IFNG) (CA) repeat, glutathione S-transferase mu 1 (GSTM1) null genotype, glutathione S-transferase pi 1 (GSTP1) rs1695, and WNT4 rs16826658 and rs2235529 [99, 100]. Contrary to this, another finding reveals that WNT4 rs16826658 including rs7515106 and rs7521902 were not associated with endometriosis, but WNT4 rs2235529 was associated with endometriosis [101]. However, a recent study claims an association between WNT4 rs7521902 and endometriosis [75]. Similarly, another study shows that there was no difference in the frequencies of GSTM1 polymorphism (null genotype) between endometriosis cases and controls in Brazil - ian women. However, polymorphism (null genotype) of theta (θ) of the glutathione S-transferase system 1 (GSTT1) was predominantly observed in the endome - triosis group than in the control group [102]. Six other polymorphisms of interest in the setting of endome - triosis include progesterone receptor (PGR) PROGINS, intercellular adhesion molecule 1 (ICAM1) rs1799969, aryl-hydrocarbon receptor repressor (AHRR) rs2292596, cytochrome family 17 subfamilies A polypeptide 1 (CYP17A1) rs743572, CYP2C19 rs4244285, and peroxi - some proliferator-activated receptor gamma (PPARG ) rs1801282 [99]. Some polymorphisms may not have any link with the development of the disease but can influ - ence the stage of the disease. Polymorphism of PvuII and XbaI in estrogen receptor (ESR1/ER-α) is associated with stage I to III endometriosis but has no correlation with the development of endometriosis [103]. Other risk fac - tors such as SNP (rs1042522) of tumor suppressor gene p53 may increase the risk of endometriosis [104]. Simi - larly, ovarian endometriosis is linked with MAP kinase- interacting serine/threonine-protein kinase 1 (MKNK1) and DNA topoisomerase III alpha (TOP3A). MKNK1 favors ectopic endometrial stromal cell (EESC) migration and invasion, whereas TOP3A favors the proliferation of EESC [105]. Irrespective of many established genetic associations of endometriosis, it was proved that the association between genetic polymorphism and endo - metriosis is subject to ethnic variation [101]. Neverthe - less, genetic association with endometriosis should not be overlooked due to the vulnerability of that particular ethnic population. Recent studies have implicated RNA in the pathogen - esis of endometriosis. The expression level of long non- coding RNA (lncRNA) was much higher in the ectopic endometrium compared to the eutopic endometrium in the majority of cases [106]. lncRNAs can promote cell migration and metastasis. They reduce apoptosis rate [107]. However, overexpression of certain types of lncRNA such as maternally expressed gene 3 (MEG3) plays a protective role by preventing endometrial cell proliferation and invasion [108]. Similar to lncRNA, another type of non-protein-coding transcript that plays Page 7 of 27 Paul et al. Middle East Fertility Society Journal (2025) 30:6 a role in endometriosis is microRNA (miRNA). lncRNA and miRNA have been found to control inflammatory responses, cell proliferation, and angiogenesis [106]. lncRNA HOTAIR favors the invasion and migration of endometrial stromal cells by acting on multiple miR - NAs [109]. miRNAs can also facilitate metastasis. Peri - toneal macrophage-derived exosomal miR-22-3p plays an important role in EESC proliferation, migration, and invasion. miR-22-3p targets sirtuin 1 (SIRT1) [110], a class III histone deacetylase. This will abolish the sup - pressing effect of SIRT1 on NF-kB expression, leading to an increased NF-kB activity [111]. NF-kB activation in macrophage and ectopic endometrial cells will trigger the synthesis of proinflammatory cytokines; this will estab - lish, maintain, and develop endometriotic lesions. NF-kB activation is implicated in “cell adhesion, invasion, angio- genesis, inflammation, proliferation, and apoptosis” [82]. Contextually, miR-202-3p, miR-411-5p, miR-29c-3p, and miR-138-5p were upregulated in peritoneal implants and rectovaginal lesions [112]. Other microRNAs of clini - cal significance are miR-95, miR-103, miR-106a, miR- 151, miR-155, miR-182, miR-183, miR-194, miR-200a, miR-200c, miR-203, miR-205, miR-210, and miR-223. Expression levels of these microRNAs were higher in endometrioid endometrial adenocarcinoma in Chinese females. Among these miRNAs, miRNA 205 had a very high expression level and has been correlated with inva - sion into muscle layers and recurrence [113, 114]. The significance of these miRNAs is evident from the finding that endometriosis has a strong correlation with endome- trioid adenocarcinoma [115]. Other miRNAs which play a role in endometriosis include miR-616-3p, miR-21-5p, and miR-194-3p. miR-616-3p favors cell proliferation and migration in endometriosis when downregulation of cir - cular RNA (circ RNA) such as circ_0000673 occurs [116]. miR-21-5p plays a role in downregulating progesterone receptor expression [117]. The endometrium of patients with endometriosis shows significant upregulation of miR-21-5p [118]. Similarly, miR-194-3p is responsible for progesterone resistance and infertility in endometriosis patients [119]. Dysregulation of the pro-inflammatory pathway plays a critical role in endometriosis. Endometrioma tran - scriptome analysis identifies epithelium, stroma, and proximal mesothelial cells to be the primary sites of dys - regulation [120]. Cytokines play an important role in the pro-inflammatory pathway involved in endometriosis. Cytokines which are implicated in endometriosis include IL-1β, IL-6, IL-10, IL-15, IL-16, IL-17A, IL-18, IL-27, IL-33, IL-37, TNF-α, NF-kB, and monocyte chemotactic protein-1 (MCP-1) [18, 120]. IL-1β can induce cyclooxy - genase-2 (COX-2) by favoring the phosphorylation of ERK, p38, and Jun N-terminal kinase (JNK). COX-2 is responsible for “cell proliferation, a low level of apoptosis, high invasion, angiogenesis, endometriosis-related pain, and infertility” . COX-2 will produce PGE2; PGE2 will pro- mote endometriosis by binding with EP2 and EP4 recep - tors. The pathological significance of COX-2 and PGE2 is evident from their higher levels in endometriotic lesions compared to normal endometrium [121]. Similarly, TNF-α and IFN-γ synergistically trigger COX-2 produc - tion in macrophages [122] and the role of macrophages in endometriosis is well documented [82, 89]. IL-1β along with IL-12 can induce the IFN-γ gene and increase the IFN-γ protein level in CD56 (bright), a subset of NK cells [123]. It is found that the presence of endometriosis or its stage has no impact on the concentration of peritoneal IL-12 [124]. Interestingly, murine model study shows that IL-12 inhibits ectopic endometriotic tissue development in the peritoneal cavity via NK cell activation [125]. IL-1β disrupts the decidual function in human endo - metrial stromal cell cultures obtained from normal control and from eutopic endometrium of patients with endometriosis. This was accompanied by rapid phos - phorylation of estrogen receptor ER-α, progesterone receptors A and B, gap junction protein, and connexin (Cx)43—leading to their cellular depletion. This will lead to decreased fertility in women [126]. IL-1β and IL-6 have been identified to cause neuroangiogenesis in endometriosis [127]. Studies have found a significantly higher serum concentration of IL-1β, IL-6, and TNF-α in women with endometriosis [128]. IL-1β was signifi - cantly higher in endometriotic tissue compared to the endometrium of the patient with endometriosis or healthy control. Similarly, endometrioma had shown a higher level of IL-1β compared to lesions of other local - izations. However, IL-6 was prevalent in both endome - triotic tissue and endometrium of patients with endometriosis. Strangely, the TNF-α level was signifi - cantly lower in endometriotic tissue compared to the endometrium of the healthy control [129]. This shows a location-specific prevalence of these cytokines in endo - metriosis. The significance of location specificity is apparent from the finding that higher serum concentra - tion of IL-6 and/or IL-8 is associated with infertility among endometriosis patients [130]. Ectopic endome - trium shows a significantly higher concentration of IL-15 but the eutopic endometrium shows a higher concentration of IL-7 [131]. IL-15 expressed by endo - metrial stromal cells downregulates granzyme B and IFN-γ in CD16+NK cells. This will prevent the killing activity of NK cells; favor invasiveness, maintain viabil - ity, and trigger the proliferation of endometrial stromal cells [132]. IFN-γ level and IFN-γ +CD4+ percentage in the peritoneal fluid were significantly higher in both early and advanced stages of endometriosis. The Page 8 of 27Paul et al. Middle East Fertility Society Journal (2025) 30:6 advanced stage of endometriosis also shows elevated levels of IL-10 and IL-10 +CD4+ cells. In this regard, it is noteworthy that IL-27 overexpressing endometrial stromal cells and macrophages induces an excess of IL- 10+CD4+ T cells. IL-27 and IL-2 play a synergistic role in promoting the growth and invasion of ectopic endothelial stromal cells by modulating IFN-γ and IL-10. Even the transcription of enzymes of ectopic endothelial stromal cells such as MMP-2, MMP-9, and prostaglandin-endoperoxide synthase 2 will be pro - moted [133]. This raises concern due to the fact that MMP-2 plays a role in endometrial cancer. Its expres - sion shows a close association with clinical stage, tumor invasion, and metastasis [134– 136]. Similarly, MMP-9 is highly expressed in endometrial cancer [136]. IL-27 promotes IL-10 production by T helper cell 17 (Th17) by c-musculoaponeurotic fibrosarcoma (c-Maf)/reti - noic acid-related orphan receptor gamma t (RORγt)/B lymphocyte-induced maturation protein-1 (Blimp-1) pathway. This leads to the progression of endometriosis [137]. Recent studies have also proved the pro-fibrotic role of IL-10 in endometriosis which includes “cell pro - liferation, collagen type I synthesis, α-smooth muscle actin positive stress fibers, and collagen gel contrac - tion” [138]. Previous studies have also proved the role of IL-10 in the development of endometriosis [139]. Another cytokine that has an active role in endometrio - sis is IL-16. It is associated with severe chronic pelvic pain in endometriosis. Serum concentration of IL-16 significantly increases as there is a shift from mild pain to chronic severe pain. This indicates a positive correla - tion between IL-16 concentration and pelvic pain [97, 98]. Peritoneal fluid from patients with advanced stage (III/IV) endometriosis shows a significantly higher IL-16 concentration compared to normal control. Peri - toneal IL-16 can induce the release of cytokines, such as IL-6, TNF-α, and IL-1β, from peritoneal fluid mono - nuclear cells (PFMC)—leading to inflammatory mani - festations [140]. In this regard, it is worth mentioning that IL-6 may have regenerative and anti-inflammatory roles via classic signaling, where only a few cells express IL-6 receptors. At the same time, IL-6 will also have a pro-inflammatory role via trans-signaling where solu - ble IL-6 receptors can stimulate any cell type [141]. Another cytokine implicated in the pathogenesis of endometriosis is IL-17A. Peritoneal fluid and plasma show a higher concentration of IL-17A compared to normal control [142, 143]. Elevated levels of IL-17A in serum and follicular fluid have some correlation with endometriosis and infertility. The stroma and the sur - roundings of the vasculature show higher concentra - tions of IL-17A in eutopic endometrium and ectopic lesions. IL-17A favors angiogenesis through VEGF and IL-8 and promotes inflammation through IL-6 and IL-1β [142, 144]. IL-8 partly favors the action of angi - opoietin-1 (Ang-1) in promoting endothelial migration and proliferation [145]. It is noteworthy that VEGF overexpression favors neovascularization accompanied by plasma leakage but Ang-1 overexpression favors enlargement of existing blood vessels without favoring plasma leakage [146]. The significance of Ang-1 is evi - dent from the finding that eutopic endometrium from women with endometriosis shows higher mRNA and protein expression of Ang-1 (P < 0.05) compared to the endometrium without endometriosis. Even the mRNA level of Ang-2 was significantly higher in the eutopic endometrium of patients with endometriosis. Increased expression of Ang-1 mRNA, Ang-2 mRNA, and Ang-1 protein makes eutopic endometrium more angiogenic [147]. However, the Ang-2 protein opposes the func - tion of Ang-1 and has an inhibitory effect on angiogen - esis [148]. Contextually, IL-1β and IL-23 can stimulate the release of IL-17 [149, 150] and the peritoneal fluid of endometriosis patients shows a higher level of IL-23 [151]. This shows the significance of a higher level of IL-23 in the peritoneal fluid, though the serum level of IL-23 in the endometriosis group was lower than in the non-endometriosis group [152]. The actual role of IL-23 in the context of endometriosis remains elusive due to the fact that IL-23 decreases IL-8 secretion. Decreased IL-8 level is believed to reduce endometrial stromal cell viability [153]. This shows that suppression of IL-8 will alleviate endometriosis because excessive stromal cell viability is a favoring factor for endometri - osis [154, 155]. However, the complexity of the role of IL-23 further increases from the consideration that an increased level of IL-23 may be the reason behind infer - tility in endometriosis patients [151]. Another cytokine implicated in endometriosis is IL-18. Peritoneal fluid from endometriosis patients shows a higher concentra - tion of IL-18 compared to non-endometriotic samples. This is related to the consequent activation of cyclooxy - genase-II in peritoneal monocytes. This is linked with the pathogenesis of endometriosis [156]. Contrary to this finding, a contemporary observation reveals a lower concentration of IL-18 in the peritoneal fluid of endometriosis patients compared to the control group. Strangely, this is also related to the pathogenesis of endometriosis [157]. Another research shows that patients with minimum or mild endometriosis did not show increased levels of peritoneal and serum IL-18 [158]. Another cytokine that plays a role in the patho - genesis of endometriosis is IL-33. Both plasma and per - itoneal levels of IL-33 are associated with deep endometriosis. IL-33 plays a significant role in inflam - mation, angiogenesis, and proliferation of lesions. The Page 9 of 27 Paul et al. Middle East Fertility Society Journal (2025) 30:6 invasiveness of human endometriotic stromal cells through membrane-bound IL-33 receptor (ST2)/ MAPK/MMP-9 pathway is also promoted by IL-33. IL-33 induces the production of profibrotic cytokines by regulatory T cells and promotes fibrogenesis [159– 162]. Another cytokine implicated in the pathogenesis of endometriosis is IL-37. It is known for its anti- inflammatory role. It inhibits adhesion, migration, and invasion of endometrial stromal cells and also sup - presses the activity of MMP-2 and MMP-9. It also sup - presses IL-1β, IL-6, IL-10, and TNF-α [163]. Contrary to this, one study has found a positive correlation between IL-37 and TNF-α levels in the peritoneal fluid of patients with endometriosis; the expression levels of both IL-37 and TNF-α were higher in endometriosis patients compared to the control group [164]. This raises concern about the actual implication of IL-37 in endometriosis because TNF-α stimulates the prolifera - tion of endometrial cells and favors angiogenesis. The level of soluble TNF-α receptor-I was higher in all stages of endometriosis; indicating the pathological role of soluble TNF-α receptor-I in endometriosis [165]. Another cytokine that takes part in the patho - genesis of endometriosis is MCP-1. The follicular fluid of infertile patients with endometriosis shows a signifi - cantly higher concentration of MCP-1 mRNA along with other cytokines such as TNF-α and IL-10. This indicates their involvement in endometriosis as well as infertility [166]. Studies have proved a significantly higher concentration of MCP-1 in serum and perito - neal fluid along with hepatocyte growth factor (HGF) and insulin-like growth factor-1 (IGF-1). Peripheral blood mononuclear cells (PBMC), PFMC, and EESC have shown significantly higher levels of MCP-1 and IGF-1 gene expression. MCP-1 and IGF-1 protein expression by PFMCs was significantly higher in endo - metriotic women compared to the control group. HGF gene and HGF protein expression by PFMC were sig - nificantly higher in endometriotic women compared to control. Similarly, gene expression of HGF by EESC was significantly higher in endometriotic women [167]. HGF promotes the proliferation and invasion of stro - mal cells. This is partly facilitated by urokinase-type plasminogen activator [168]. Similarly, IGF-1 favors endometriosis by stimulating the growth of endome - trial cells and preventing their apoptosis. IGF-1 signal - ing is also responsible for hyperalgesia [169]. Other mediators of endometriosis include fibrino - gen and leptin. Fibrinogen alpha chain concentration in serum and its expression level by the endometrial tissue determine the severity of the pathogenesis of endome - triosis. A positive correlation has been observed between fibrinogen alpha chain concentration and endometriosis [170]. Similarly, higher leptin concentrations in the peri - toneal fluid and follicular fluid of women with endome - triosis are suggested to play a role in endometriosis [171]. The murine model study has proved that a deficiency of leptin and its receptor can suppress endometriosis [172]. All these molecular targets (Table  1) together can aggra - vate the disease condition. The druggable molecular tar - gets are shown in Fig. 1. Plants in the management of endometriosis Nature with its variety of plants has the potential to treat many diseases. Modern technology of identification and isolation of phytoconstituents from plant sources has emerged as a promising alternative to treat many disor - ders. Different phytoconstituents which can target the mediators of endometriosis and alleviate the disease are mentioned below. Phytoconstituents acting as progestin and modulating progesterone receptor B Phytoprogestins such as apigenin (a flavonoid) and kaempferol (a flavonoid) show progestogenic activity. They upregulate zinc finger and BTB domain-containing 16 (ZBTB16) expression. Apigenin significantly (p < 0.05) increases the level of ZBTB16 protein [173]. ZBTB16 expression is required for decidualization, a step cru - cial for pregnancy [174]. Apigenin shows progesterone receptor B modulatory activity. It has mixed progester - one receptor agonist activity and can suppress estrogen receptor-mediated uterine proliferation [175]. Apigenin shows a potent anti-angiogenic effect and can reduce microvessel density [176]. Apigenin can suppress the pro- liferation and induce apoptosis of endometriosis cell lines such as VK2/E6E7 and End1/E6E7. Apigenin has induced dysregulation of mitochondrial membrane potential. This led to an increase in cytosolic calcium. Calcium and other pro-apoptotic proteins such as Bax, Bak, and cytochrome C have induced apoptosis in VK2/E6E7 cells. However, apoptosis of End1/E6E7 cells was triggered by Bax and cytochrome C. Apigenin is also found to possess an anti-inflammatory effect [177]. This shows the pos - sibility and significance of Apigenin in the treatment of endometriosis because progesterone-mediated healing of endometriosis involves inhibition of angiogenesis, uter - ine cell proliferation, and inflammation [178] (Table 2). Phytoconstituents acting as estrogen and targeting ER‑β Phytoestrogens such as genistein and coumestrol (iso - flavonoids) have a higher affinity for ER-β compared to ER-α. Genistein shows a 30-fold higher relative estro - genic potency on ER-β compared to the potency on ER-α. Similarly, coumestrol shows a higher binding affinity for ER-β receptors [179]. The murine model study has Page 10 of 27Paul et al. Middle East Fertility Society Journal (2025) 30:6 Table 1 Molecular/therapeutic target for the treatment of endometriosis Therapeutic target Role in endometriosis Reference Progesterone receptor A Inhibits progesterone receptor B expression, negative regulation of progesterone receptor B, endometrial hyperplasia, chronic pelvic pain, infertility, inflammatory disorders, and cancer [62, 63, 65, 66] Progesterone receptor B Prevents endometrial hyperplasia and inflammation [62] ER-α receptor Endometrial proliferation, pain, recurrence, and endometrial cancer [69, 70, 71] ER-β receptor Opposing effect on the function of ER-α receptor [70, 182, 184] miR-194-3P Progesterone resistance and infertility [119] miR-21-5p and lncRNA Inflammatory responses, cell proliferation, angiogenesis, cell migration, and reduced apoptosis [106, 107, 118] lncRNA MEG3 Prevents endometrial cell proliferation and invasion [108] lncRNA HOTAIR Favors invasion and migration of endometrial stromal cells through miRNAs [109] miR-95, miR-103, miR-106a, miR-151, miR-155, miR-182, miR- 183, miR-194, miR-200a, miR-200c, miR-203, miR-205, miR-210 and miR-223 Invasion into muscle layers, recurrence, endometrioid adeno- carcinoma [113, 114, 115] miR-202-3P , miR-411-5P , miR-29c-3P , miR-138-5P Peritoneal implant and rectovaginal lesions [112] miR-616-3p Favors cell proliferation and migration in endometriosis [116] VEGF, CD31, Tie2, Ve-cadherin, FAK/MAPK/HIF-1α axis Angiogenesis [77, 84, 85] Ang-1 mRNA and protein, Ang-2 mRNA Eutopic endometrium angiogenesis [147] HIF-1α Endometriotic lesions [84, 85] Nrf2/Keap1/HO1 axis Endometriotic lesions [86] NF-kB Synthesis of proinflammatory cytokines and formation of endo- metriotic lesion [82] MMP-1 Invasion of endometrial cells and vascularization [92] MMP-2 Endometriosis and endometrial cancer [134, 135, 136, 163] MMP-3 Invasion of endometrial cells, vascularization, advanced endo- metriosis, and infertility [93, 94, 95] MMP-9 Endometriosis and cancer diseases including ovarian cancer and endometrial cancer [88, 90, 91, 136] MKNK1 EESC migration and invasion [105] TOP3A Proliferation of EESC [105] IL-1β, IL-6, IL-10, IL-15, IL-16, IL-17A, IL-18, IL-27, IL-33, IL-37, TNF-α, MCP-1 Inflammation [18, 120] IL-1β, IL-6 and IL-8 Infertility associated with endometriosis [126, 130] IL-2 and IL-27 Growth and invasion of EESC increases transcription of enzymes of EESC such as MMP-2, MMP-9, and prostaglandin-endoperox- ide synthase 2 [133] IL-10 Pro-fibrotic role and promotes endometriosis [138, 139] IL-15 Invasiveness, viability, and proliferation of endometrial stromal cell [132] IL-16 Severe pain in endometriosis [97, 98] IL-17A Angiogenesis through VEGF and IL-8 promotes inflammation through IL-6 and IL-1β [142, 144] IL-33 Inflammation, angiogenesis, proliferation of lesions, invasiveness of human endometriotic stromal cell, production of profibrotic cytokines [159, 160, 161, 162] COX-2, PGE2, EP2 and EP4 receptors Cell proliferation, apoptosis (low level), high invasion, angiogen- esis, endometriosis-related pain and infertility [121] IFN-γ, TNF-α COX-2 induction, endometrial cell proliferation, and angiogen- esis [122, 165] MCP-1 Inflammatory changes in endometriosis, infertility [166, 167] HGF, urokinase-type plasminogen activator Proliferation and invasion of stromal cells [167, 168] IGF-1 Endometrial cell growth prevents endometrial cell apoptosis and hyperalgesia [167, 169] Page 11 of 27 Paul et al. Middle East Fertility Society Journal (2025) 30:6 proved that genistein has significantly (P < 0.05) reduced the expression of ER-α receptor, but there was a signifi - cant (P < 0.05) increase in the expression of ER-β in peri - toneal endometriosis [180]. Alaria, a seaweed can lower estrogen levels in the body, reducing the risk of endome - triosis [181]. Phytoconstituents targeting MAPK pathway, MKNK1, and TOP3A Quercetin (a flavonoid) significantly decreases endo - metriotic cell proliferation by suppressing the phospho - rylation of p38MAPK/ERK-1/2/phosphatidyl inositol-3 kinase (PI3K)/protein kinase B (AKT). It also causes a decrease in the expression of cyclin D1, which plays a role in cell proliferation [182]. The anti-proliferation mechanism is somewhat complicated because p38MAPK is known to negatively regulate cyclin D1 [183]. Never - theless, it has proved its role as an anti-proliferation agent. It induces cell apoptosis by destroying mitochon - drial membrane potential and inducing DNA fragmen - tation. It generates reactive oxygen species (ROS) and causes lipid peroxidation of the proliferating cells, lead - ing to apoptosis. Quercetin also reduces the size of endo - metriotic lesions [182]. It also activates the ER-β receptor to interrupt the endometrial proliferative role of the ER-α receptor [182, 184]. The best part of quercetin is that it is safe for normal cells [182]. Similarly, curcumin (a poly - phenol) is also an AKT inhibitor [185]. Genistein can downregulate MAPK activation [186]. The network anal - ysis technique suggests that ursolic acid may target the Table 1 (continued) Therapeutic target Role in endometriosis Reference Fibrinogen alpha chain Severity of pathogenesis of endometriosis [170] Leptin and its receptor Favors endometriosis [171, 172] Fig. 1 Molecular targets for the treatment of endometriosis Page 12 of 27Paul et al. Middle East Fertility Society Journal (2025) 30:6 Table 2 Phytoconstituents effectively regulating the molecular targets Therapeutic target Phytoconstituents of therapeutic significance Reference Progesterone receptor B Apigenin modulates progesterone receptor B [175] ER-α receptor Genistein significantly reduces the expression of the ER-α receptor [180] ER-β receptor Genistein significantly increases the expression of the ER-β receptor [180] miR-21-5p and lncRNAs Saponins significantly decrease miR-21 −5p expression. Res- veratrol can increase and decrease the expression of lncRNAs such as MEG3 and H19, respectively [108, 118, 196] lncRNA HOTAIR Xiaoji decoction significantly decreases lncRNA HOTAIR expression [203] miR-95 Genistein can downregulate miR-95 [190, 191] miR-103 Anthocyanins, flavonols, and derivatives of phenolic acids can reduce miR-103 expression [192] miR-223 Genistein downregulates miR-223 [194, 195] miRNA 155, miRNA 138 Curcumin significantly decreases the miRNA expression levels of miRNA 155 and miRNA 138 [189] miR-183 Gleditsia sinensis extract significantly suppresses miR-183 [193] VEGF, CD31, Tie2, FAK/MAPK/HIF-1α axis Resveratrol decreases VEGF expression; Apigenin strongly suppresses VEGF-A/VEGFR2 pathway; Polysaccharide from Lentinus edodes downregulates CD31 expression; 5α-hydroxycostic acid and hydroxyisocostic acid inhibit Tie-2 phosphorylation; Quercetin suppresses p38MAPK/ERK-1/2/ PI3K/ protein kinase B (AKT); Apigenin strongly suppresses HIF-1α [176, 182, 202, 204, 205] Ang-1 mRNA and protein Resveratrol decreases Ang-1 mRNA [202] Ang-2 mRNA 5α-hydroxycostic acid and hydroxyisocostic acid can suppress Ang-2 mRNA expression [205] Nrf2/Keap1/HO1 axis Naringenin decreases the expression of Nrf2 and HO1 but increases Keap1 expression [86] MMP-1, MMP-2, MMP-3, MMP-9 Kaempferol significantly decreases MMP-1 and MMP-3 protein expression; Curcumin pretreatment inhibits MMP-2 activity; Withaferin-A downregulates the expression of MMP-2 and MMP-9; Quercetin can suppress MMP-2 and MMP-9; Naringenin suppresses both MMP-2 and MMP-9, Resveratrol reduces MMP-2; Genistein inhibits the production and activity of MMP-2 and MMP-9 [86, 186, 202, 206, 207, 219, 222, 223] MKNK1 Ursolic acid targets MKNK1 and may prevent EESC migration and invasion [187] TOP3A Shogaol, demethoxycurcumin, capsaicin, ellagic acid, 6‐para- dol, 6‐gingerol, carnosic acid, and curcumin act as antago- nists for human DNA TOP3A [188] IL-1β, IL-2, IL-6, IL-8, IL-10, IL-17A, IL-18, IL-33, TNF-α, NF-kB, IFN-γ, MCP-1 Withaferin-A reduces the levels of IL-1β, IL-6, TNF-α and down- regulates NF-kB signaling; Resveratrol suppresses IL-8 release; Quercetin and tuberostemonine-O can significantly inhibit IL-2 production; Quercetin significantly reduces protein level and gene expression of IFN-γ; Apigenin decreases IL-10 and TNF-α expression; Rosmarinic acid can suppress the production of IL-17A; Curcumin can significantly suppress IL-18 production; Licochalcone-A suppresses IL-1β and IL-18 expression; Apigenin and luteolin suppress the production of IL-33; Quercetin suppresses MCP-1 mRNA and protein expression levels [206, 208, 209, 210, 211, 212, 213, 214, 215] Page 13 of 27 Paul et al. Middle East Fertility Society Journal (2025) 30:6 MKNK1 gene and prevent EESC migration and invasion [187]. In silico studies have proved that “shogaol, dem - ethoxycurcumin, capsaicin, ellagic acid, 6‐paradol, 6‐ gingerol, carnosic acid, and curcumin” can bind strongly with human DNA TOP3A and act against TOP3A [188] (Table 2). Phytoconstituents targeting miRNA Saponins (glycosides of triterpenes and steroids) can sig - nificantly (p = 0.022) decrease miR-21 −5p expression in human endometriotic stromal cells. This will sup - press the proliferation and also induce the apoptosis of endometriotic cells by unleashing caspase-3. Saponins can significantly (p < 0.05) induce caspase-3 expression [118]. Curcumin has been found to significantly decrease the miRNA expression levels of miRNA 155 (P = 0.002), miRNA 138 (P = 0.024), and miRNA16 (P = 0.0001) [189]. Genistein can downregulate miR-95 [190, 191]. A com - bination of polyphenols such as anthocyanins, flavonols, and derivatives of phenolic acids can reduce the expres - sion of miR-103 [192]. Extract of Gleditsia sinensis can significantly (P < 0.01) suppress the expression of miR- 183 [193]. Genistein can also downregulate the expres - sion of miR-223 [194, 195] (Table 2). Phytoconstituents targeting lncRNA Resveratrol at 200  µM concentration can increase the expression of several lncRNAs such as MEG3, pituitary tumor-transforming 3 pseudogene (PTTG3P), BST2 interferon-stimulated positive regulator (BISPR). Res - veratrol at 50 µM concentration can increase lncRNAs such as metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and conserved gene cluster H19 locus (H19) but at 200 µM concentration can decrease the expression of H19. Similarly, the expression of growth arrest-specific transcript 5 (GAS5) was sig - nificantly decreased. A decreased expression of H19 has been beneficial in inducing apoptosis and death of cancer cells [196]. MEG3 stops endometrial cell prolif - eration and invasion [108]. Thus, the beneficial role of resveratrol seems to be partly dependent on its mod - ulating effects on the expression levels of MEG3 and H19. The actual role of resveratrol is much more com - plicated because the expression level of BST2 is very high in ectopic endometrium. BST2 is responsible for EESC proliferation, migration, and lymphangiogen - esis during endometriosis. BST2 also inhibits apoptosis [197]. Similarly, MALAT1 is responsible for the sur - vival of endometrial stromal cells under hypoxic condi - tions. Hypoxia induces HIF‐ 1α, and HIF-1α upregulates MALAT1 [198]. GAS5 can suppress NF-kB [199] and represses endometrial cancer [200]. H19 is responsible for infertility, endometriosis, uterine fibroids, and many other disorders [201]. Thus, the mechanism behind the beneficial role of resveratrol through lncRNAs is still elusive. Nevertheless, resveratrol has the therapeutic potential to treat endometriosis. This is proved by a finding where resveratrol could significantly decrease cell viability (P = 0.0065 to P = 0.0180) and cell migra - tion (P < 0.001 to P = 0.0225) in endometriosis. Res - veratrol could significantly increase the number of apoptotic cells (P = 0.0031 to P = 0.0432) in endome - triotic cell lines [202]. Contextually, Xiaoji decoction prepared from “Psoralea corylifolia L., Coriolus ver - sicolor (L. ex Fr.) Quel., Astragalus membranaceus (Fisch.) Bge, Curcuma phaeocaulis Val., Buthus marten - sii Karsch, Scolopendra subspinipes mutilans L. Koch, Rheum palmatum L., Hedyotis diffusa Willd” has been found to significantly (P < 0.05) decrease the expression of lncRNA HOTAIR [203] (Table 2 ). Table 2 (continued) Therapeutic target Phytoconstituents of therapeutic significance Reference COX-2, PGE2 and EP4 receptors Withaferin-A downregulates COX-2; Kaempferol significantly suppresses the mRNA expression of COX-2; Granatin-B and Kaempferol significantly suppress the expression of PGE2; Xiaoji decoction prepared from “Psoralea corylifolia L., Coriolus versicolor (L. ex Fr.) Quel., Astragalus membranaceus (Fisch.) Bge, Curcuma phaeocaulis Val., Buthus martensii Karsch, Scolopendra subspinipes mutilans L. Koch, Rheum palma- tum L., Hedyotis diffusa Willd” significantly decreases mRNA and protein expression levels of EP4 [203, 206, 219, 221] HGF, urokinase-type plasminogen activator Quercetin suppresses HGF signaling; resveratrol suppresses mRNA expression of urokinase plasminogen activator [224, 225] IGF-1 Apigenin inhibits IGF-1-induced activation of IGF-1R [226] Fibrinogen alpha chain Curcumin lowers plasma fibrinogen [227] Leptin and its receptor Curcumin inhibits leptin expression and secretion; resveratrol reduces mRNA expression and secretion of leptin [228, 229] Page 14 of 27Paul et al. Middle East Fertility Society Journal (2025) 30:6 Phytoconstituents targeting VEGF, CD31, Tie‑2, and Ang‑2 mRNA Resveratrol can decrease the expression levels of VEGF (P = 0.0052 to P = 0.0243) and Ang-1 mRNA (P < 0.001 to P = 0.0382) [202]. Genistein has been found to decrease VEGF-induced activation of JNK and p38 but not ERK- 1/2. This leads to a decreased angiogenesis [186]. Api - genin strongly suppresses HIF-1α expression and its downstream VEGF-A/VEGFR2 pathway [176]. Cell line studies have shown that purified polysaccharides from the fruit bodies of Lentinus edodes can downregulate the expression of CD31 [204]. 5α-hydroxycostic acid and hydroxyisocostic acid (two eudesmane-type sesquiterpe - nes from the herb Laggera alata) can inhibit Tie-2 phos - phorylation. 5α-hydroxycostic acid and hydroxyisocostic acid can significantly (P < 0.005) suppress the expression level of Ang-2 mRNA [205] (Table 2). Phytoconstituents targeting cytokines and others Withaferin-A (a steroidal lactone) reduces the levels of IL-1β, IL-6, and TNF-α [206]. Similarly, quercetin decreases mRNA and protein levels of IL-1β induced IL-6 in a dose-dependent manner [207]. Resveratrol sup - presses inflammation in endometriosis by suppressing TNF-α induced IL-8 release [208]. Quercetin (P < 0.0005) and tuberostemonine-O (P < 0.005) can significantly inhibit IL-2 production. Quercetin also significantly (P < 0.0005) reduces the mRNA and protein expression of IFN-γ [209]. Apigenin can significantly (P < 0.001) decrease the expression of both IL-10 and TNF-α [210]. Rosmarinic acid can suppress the production of IL-17A [211]. Curcumin can significantly (P < 0.0001) suppress IL-18 production [212]. Licochalcone-A suppresses IL-1β and IL-18 expression [213]. Apigenin and luteolin can significantly (P < 0.05) suppress the production of IL-33, but apigenin was better than luteolin [214]. Quercetin can significantly (P < 0.05) suppress the mRNA and pro - tein expression of MCP-1 [215] (Table 2). Phytoconstituents targeting NF‑kB/COX‑2 or Nrf2/Keap1/ HO1 axis Andrographolide (a diterpenoid lactone) suppresses the role of NF-kB by inhibiting its DNA-binding ability and subsequent release of COX-2, tissue factor, and nerve growth factor. This will lead to a decrease in ectopic endometrial cell proliferation and a reduction in the size of ectopic lesions. Andrographolide has been found to reduce pain in the murine modal of endometriosis [216, 217]. Curcumin also partly inhibits NF-kB [185]. Simi - larly, withaferin-A downregulates COX-2/NF-kB sign - aling and suppresses the proliferation of endometriotic lesions [206]. Murine model studies have proved that flavonoids (eriodictyol, glycitin, 5-O-methylgenistein, ( +)-catechin 7-O-beta-D-xyloside, (-)−8-prenylnarin - genin, and ( ±)-naringenin) from Phaleria macrocarpa can suppress the growth of endometriosis lesions [218]. Previous studies with quercetin have proved that it can suppress MAPK and NF-kB signaling pathways [207] and consequent endometriotic lesions [182]. Naringenin prevents endometriotic lesions by modulating Nrf2/ Keap1/HO1 axis. It decreases the expression levels of Nrf2 and HO1 but increases the expression of Keap1 in a dose-dependent manner [86]. Kaempferol significantly (P < 0.05) suppresses the mRNA expression of COX-2 [219]. Gambogenic acid has the potential to downregu - late the expression of COX-2 mRNA [220] (Table 2). Phytoconstituents targeting PGE2 and its receptors Granatin-B can significantly (P < 0.001) suppress the expression of PGE2 [221]. Kaempferol can also signifi - cantly (P < 0.05) suppress the production of PGE2 [219]. Xiaoji decoction prepared from “Psoralea corylifolia L., Coriolus versicolor (L. ex Fr.) Quel., Astragalus mem - branaceus (Fisch.) Bge, Curcuma phaeocaulis Val., Buthus martensii Karsch, Scolopendra subspinipes mutilans L. Koch, Rheum palmatum L., Hedyotis diffusa Willd” has been found to significantly (P < 0.05) decrease the mRNA and protein expression of EP4 [203] (Table 2). Phytoconstituents targeting MMPs Kaempferol can significantly (P < 0.05) decrease MMP -1 and MMP-3 protein expression levels [219]. Curcumin pretreatment (48 mg/kg body weight) plays a protective role against endometriosis by inhibiting MMP-2 activity [222]. Similarly, withaferin-A is very effective in down - regulating the expression levels of MMP-2 and MMP-9. It also suppresses their activities in ectopic endometrium [206]. Similarly, quercetin can suppress MMP-9 [207]. As per a recent study, quercetin may suppress MMP-2, MMP-9, and other proteins to suppress the proliferation of EESC [223]. Naringenin can suppress both MMP-2 and MMP-9 and prevent invasion of endometrial cells [86]. Resveratrol reduces MMP-2 (P < 0.001 to P = 0.0180) [202]. Genistein inhibits VEGF augmented secretion and activity of MMP-2 and MMP-9 [186] (Table 2). Phytoconstituents targeting HGF, urokinase‑type plasminogen activator, IGF‑1, fibrinogen alpha chain, leptin, and its receptor Quercetin can suppress HGF signaling by suppressing the AKT pathway [224] and resveratrol can suppress mRNA expression of urokinase plasminogen activator [225]. Apigenin can inhibit IGF-1-induced activation of the IGF-1 receptor (IGF-1R) and subsequent signal - ing [226]. Curcumin injection has been found to lower plasma fibrinogen concentration [227]. Curcumin can Page 15 of 27 Paul et al. Middle East Fertility Society Journal (2025) 30:6 also inhibit the expression and secretion of leptin [228]. Similarly, resveratrol can reduce the mRNA expression of leptin and its secretion [229] (Table 2). Plant extracts which can alleviate endometriosis Extracts of Achillea biebersteinii and Artemisia princeps (family Asteraceae), Euterpe oleracea (family Arecaceae), Prunella vulgaris (family Lamiaceae), Tripterygium wil - fordii (family Celastraceae), etc., may prevent endome - triosis and improve the quality of life [181]. Effects of phytoconstituents on different molecular targets for the treatment of endometriosis are shown in Table 2 and Fig. 2. Effects of phytoconstituents on infertility Apigenin can upregulate SIRT1. This will reduce oxida - tive stress and delay the aging of postovulatory oocytes [230]. Apigenin also protects and restores ovarian func - tion in murine models of polycystic ovary syndrome [231]. Genistein has a protective role in female mice fertility [232]. Resveratrol supplementation in human embryo culture medium can significantly improve embryo quality in older women over 40  years of age [233]. Anthocyanins can reduce the risk of gestational diabetes mellitus (GDM) [234] which will be increased by endometriosis [32]. The murine model study has proved that quercetin inhibits endothelin-1 and endothelin-1 type A receptors and improves the quality of pregnancy by reducing hypertension resulting from reduced uterine perfusion [235]. Impaired uterine perfusion is strongly associated with ovarian endometrioma [236] and infertil - ity [237]. Naringenin has a renoprotective effect on GDM [238]. Kaempferol can oppose the effects of oocyte aging on fertilization capacity [239]. Ursolic acid can moder - ately reduce the risk of fetal development defects in GDM [240]. Curcumin can manage GDM and fetal growth restriction [241], which are the pathological complica - tions of endometriosis [32, 242]. Intravenous ellagic acid has increased the frequency of abortion in pregnant mice [243]. This raises concerns regarding pregnancy. Car - nosic acid regulates oxidative stress and improves early porcine embryonic development [244]. In  vitro study Fig. 2 Therapeutic effects of different phytoconstituents Page 16 of 27Paul et al. Middle East Fertility Society Journal (2025) 30:6 has shown that luteolin can improve porcine embryonic development by counteracting oxidative stress [245].

The success of endometriosis treatment is dependent on the proper understanding of the pathogenesis. Though much has been understood, certain mechanisms are con - troversial and elusive. There are contradictory findings about the expression levels of progesterone receptors in eutopic endometrium [59–61]. The significance of the above information is further increased by the finding that eutopic endometrium shows greater proliferation abil - ity, implantation, and angiogenesis compared to ectopic endometrium. Interestingly, eutopic endometrium deter- mines the fate of the endometrial tissue, either to survive or to die outside the uterus and become ectopic endome - trium. Eutopic endometrium may be the reason behind infertility in endometriosis [147, 246]. It is noteworthy that progesterone inhibits the activation of NK cells [247]. Progesterone particularly suppresses the immune response during pregnancy. Progesterone induces cas - pase and destroys peripheral blood NK cells; this will favor pregnancy [248]. Notably the level of progesterone shows a progressive increase from the first trimester to the third trimester [65]. Decreased peripheral NK cell cytotoxicity is associated with endometriosis [249]. NK cells prevent the development of ectopic endometriotic tissue in the peritoneal cavity [125]. Progesterone also increases the number of NK cells, and the induction of NK cells in the endometrium is progesterone-dependent. The count of NK cells increases even when pregnancy ensues and NK cells are described to have a protective role during pregnancy. The secretory phase of the men - strual cycle (non-pregnant) shows an increased proges - terone level and an increased number of NK cells [250]. This shows the complex effect of progesterone on the NK cell population. This may raise concern about the practi - cal implications of progesterone therapy in patients with eutopic endometrium with differential expression levels of progesterone receptors. This finding shows a scope for future research to overcome the ambiguity and have bet - ter therapeutic outcomes. The apparent negative role of progesterone receptor A in endometriosis, as well as in pregnancy among endo - metriosis patients [62, 63, 65, 66], raises demand for the identification of novel phytoconstituents as progesterone receptor A antagonists. Many plant extracts have been found to have an antiprogesterone effect. These include “Cortex eucommiae, Folium artemisiae argyi, Glycyr - rhiza uralensis, Euscaphis japonica, Ailanthus altissima, Dioscorea opposite, Angelica sinensis, Atractylodes mac - rocephala koidz and Scutellaria baicalensis” [251]. Nev - ertheless, no single phytoconstituent has been identified and isolated as a selective progesterone receptor A antag- onist. Identification of active phytoconstituents from these plants and proving their selectivity as progesterone receptor A antagonists may improve the treatment strat - egy for endometriosis. Similarly, the impact of apigenin on miR-194-3P was not established. As miR-194-3P is responsible for progesterone resistance [119] and api - genin can modulate progesterone receptor [175], hence, future research unveiling the effect of apigenin on miR- 194-3P will explain its mechanistic pathway in a better way. Findings with respect to the expression levels of IL-18 in endometriosis are controversial. There are many con - tradictory evidences [156, 157]. The correlation between IL-37 and TNF-α is also controversial. As per one study, IL-37 suppresses TNF-α [163], whereas, the other study shows a positive correlation between IL-37 and TNF-α levels [164]. Thus, treatment modalities targeting IL-37 may have dichotomous outcomes. Similarly, the role of IL-12 in the context of endometriosis is elusive. It can increase the production of IFN-γ in NK cells [123] and NK cells secrete IFN-γ and TNF-α [252]. The role of IFN-γ and TNF-α in COX-2 induction, proliferation of endometrial cells, angiogenesis, invasion, pain, and infertility is well established [121, 122, 165]. Strangely, IL-12 inhibits peritoneal endometriosis via activation of NK cells [125]. Thus, targeting IL-12 or NK cells to treat endometriosis may have unexpected outcomes unless further clarity is obtained regarding their actual roles in endometriosis. The speculation on unexpected therapeu- tic outcomes following NK cell targeting is also corrobo - rated by a very recent study [253]. Thus, future research to untangle the complex relationship will help to achieve better therapeutic outcomes. The role of genetic mutation in endometriosis is subject to ethnic variation as can be seen with respect to WNT4 rs16826658 [99–101]. Thus, the effects of every genetic mutation in the context of endometriosis should be deeply studied among the worldwide population to iden - tify the susceptible ethnic group. This will help to initiate the therapy at an early age and maximize the therapeutic outcome. Higher expression of Ang-2 mRNA in eutopic endome- trium seems to favor angiogenesis [147] but other study finds that Ang-2 protein has an inhibitory effect on angi - ogenesis [148]. Interestingly, Ang-2 favors the sprouting of blood vessels in conjugation with VEGF. Ang-2 favors the production of MMPs leading to endometriosis [254]. The role of Ang-2 in neovascularization and pathologi - cal progression of endometriosis is largely dependent on VEGF and MMPs. Therefore, phytoconstituents may suppress its pathological impact by targeting VEGF and MMPs. This above controversy opens the door for future Page 17 of 27 Paul et al. Middle East Fertility Society Journal (2025) 30:6 research where the downregulating effect of any phyto - constituent on VEGF and its subsequent effect on Ang- 2-induced angiogenesis can be studied. The actual role of quercetin on p38MAPK is compli - cated because one study reports that quercetin can sup - press p38MAPK [182] whereas, another study reports that it has no effect on the p38MAPK pathway [224]. This demands further research on the existence and role of confounding variables. There are chances of many future researches with phy - toconstituents because many of them were not tested for their potential to suppress the expression of miRNAs to treat endometriosis. Similarly, COX-2 inhibitory phyto - constituents such as farnesiferol A, piperine, cedrelanol, usnic acid [255], and gambogenic acid [220] should be tested to unveil their hidden potential to treat endome - triosis. Similarly, the identification of newer phytocon - stituents that can target IL-15, IL-16, IL-27, and IL-37 may have positive outcomes on the treatment of endo - metriosis. The scope of research further increases as very little data are available on the direct effect of shogaol, demethoxycurcumin, capsaicin, withaferin-A, 6‐paradol, tuberostemonine-O, rosmarinic acid, and licochalcone-A on pregnancy. In this regard, it is worth mentioning that the negative effect of ellagic acid in pregnant mice [243] may be ignored and outweighed by its protective role in endometriosis and by the combined effects of other preg- nancy-favoring phytoconstituents. This prediction opens a narrow room for research where ellagic acid can be tried against the combined potency of other pregnancy- favoring phytoconstituents. Potential toxicity and safety concerns of these phy - toconstituents have been addressed on the basis of the following reports. Data from animal and human studies show that apigenin is quite safe at high doses and no tox - icity has been reported [256, 257]. Similarly, a mixture of genistein, daidzein, and glycitein has shown minimal tox- icity in post postmenopausal women at a very high dose (16  mg/kg body wight) [258]. The murine model study has proved that genistein did not show mutagenic or clas- togenic effects; this gave the answer to a concern raised on its mutagenic or clastogenic properties [259]. Resvera- trol has shown an excellent safety profile at 1 gm dosing in a short-term course, adverse effects may arise in non- alcoholic fatty liver disease at a dose of 2.5 g or more/day. Adverse effects include nausea, vomiting diarrhea, and liver dysfunction [260]. Other studies also found resvera - trol to be safe for human consumption [261]. No much data could be retrieved for 5α-hydroxycostic acid and hydroxyisocostic acid. However, in non-toxic doses, they were able to suppress human umbilical vein endothelial cell proliferation induced by VEGF and vessel formation in zebrafish embryos [205]. Anthocyanins obtained from grape skin extract have been declared safe at 2.5  mg/ kg by the Joint FAO/WHO Expert Committee on Food Additives. Animal studies have also shown a wide mar - gin of safety [262]. Clinical trials have shown the benefi - cial effects of quercetin and found it safe for human use [263]. In general, oral intake of quercetin is considered safe in humans [264]. Naringenin has been found safe in humans at an oral dose range of 150 to 900 mg [265]. Preclinical and clinical studies have shown low toxicity and a wide margin of safety for kaempferol [266]. The murine model study has shown that withaferin-A is safe at 2000  mg/kg [267]. Preclinical studies and clinical tri - als show that ursolic acid in nanoparticle form can have better therapeutic effects without any serious adverse effects [268]. Shogaol has been found to be a novel phy - toconstituent; it shows no toxicity to normal cells at a dose that is lethal for cancer cells [269]. Phase 1 clinical trial has shown that 8000 mg of curcumin for 3 months did not produce any toxicity [270]. Curcuma extract has also been enrolled in clinical trials to determine its effi - cacy in alleviating endometriosis-associated pain (Clini - calTrials.gov ID NCT04150406). Similarly, the safety profile of demethoxycurcumin is understood from the fact that there are many commercial preparations avail - able that contain curcumin, demethoxycurcumin, and bisdemethoxycurcumin in the ratio of 66:23:11. Dem - ethoxycurcumin is used in the food industry and is also a folk medicine and found to have a neuroprotective role [271]. Capsaicin powder taken by oral route was well tol - erated by patients suffering from unexplained chronic cough and airway symptoms [272]. Ellagic acid has been kept under the “generally recognized as safe” category by USFDA for human consumption [273]. 6-paradol has been enrolled in clinical trials and found to be effec - tive without any adverse effects [274]. Patients treated with 6-gingerol did not show any toxicity during a phase II randomized double-blind placebo-controlled study [275]. There is no data available on the safety profile of oral/parenteral formulation of carnosic acid but pre - clinical study shows a minimal toxicity of carnosic acid. The LD50 value as per the acute oral toxicity study is 7100 mg/kg in mice [276]. The safety profile of carnosic acid and rosmarinic acid can be understood from the enrolment of rosemary extract in phase 2 clinical trials for the management of periodontitis (ClinicalTrials.gov ID NCT06601608). Similarly, rosemarinic acid has been incorporated as a dietary supplement to battle fatigue in cancer patients and it was under phase 3 trial (Clinical - Trials.gov ID NCT04546607). The availability of data on tuberostemonine-O toxicity in humans is less, but ani - mal studies show that tuberostemonine can be given by both oral and intraperitoneal routes in guineapigs, but the efficiency is better when given by intraperitoneal Page 18 of 27Paul et al. Middle East Fertility Society Journal (2025) 30:6 route [277]. Similarly, luteolin nanoethosomes is effec - tive by the oral route; such formulation has addressed the issues with low oral bioavailability of luteolin [278]. No data related to the safety profile of luteolin on humans could be retrieved. The safety of luteolin can only be pre - dicted from its enrollment in numerous clinical trials with different pathological conditions (ClinicalTrials.gov ID NCT06047899, ClinicalTrials.gov ID NCT05204407). The results of these trials have not been published yet. Similarly, no data could be retrieved related to the safety of granatin-B on humans but there are certain preclinical studies. There are three clinical trials that are reported to date with licochalcone-A. The trials were conducted in the context of human oral squamous cell carcinoma and acne. One of the trials represents phase 3 enrollment (ClinicalTrials.gov ID NCT03292822, ClinicalTrials.gov ID NCT04002024, ClinicalTrials.gov ID NCT02173054). There is a scarcity of safety data for some phytoconstit - uents in humans; because very little research has taken place with these phytoconstituents. This shows a broad scope of research in the future. The future direction of research will be towards the generation of safety, compatibility data, and the deter - mination of the synergistic potential of these phytocon - stituents using Caenorhabditis elegans [279]. This will be followed by the determination of the combined safety/ toxicity of these phytoconstituents and the determination of therapeutic efficacy in cell lines and animals. The limitations of translating these findings into human therapy are increased by the scarcity of clinical data in this context. Hence, it will be a challenging task due to the novelty of the study. Nevertheless, these limitations open newer avenues for many research. To envisage the scope of phytoconstituents in the con - text of emerging concepts of endometriosis therapy, it is necessary to understand the mechanism of action of emerging therapies/concepts. Some emerging strate - gies/concepts to treat endometriosis include photody - namic therapy (PDT), hyperthermia treatment (HTT), gene therapy, immunotherapy, stem cell treatment, etc. The principle of PDT therapy depends on the production of ROS, photo-oxidation of target cells, and their death. HTT increases the vulnerability of cancer cells to chemo and radiation therapy by inhibiting DNA repair enzymes. Gene therapy for endometriosis is expected to make a dif- ference in the management of endometriosis. However, the gene therapy of endometriosis is not yet practiced rather can be seen in the preclinical studies. Gene therapy targets endometriotic lessions and VEGF-A gene activity. Gene therapy also employs miRNAs, whereas immune therapy depends on the recruitment of macrophages to ectopic lesions and macrophage-mediated engulfment of abnormal endometrial cells. Stem cell therapy employed in mice has shown promising results and has been found to have anti-inflammatory effects [280]. It has been found that quercetin generates ROS and induces apoptosis of endometriotic cells. Quercetin also reduces the size of endometriotic lesions. Quercetin also induces DNA frag - mentation [182]. Thus, quercetin can mimic the mecha - nism of action of PDT and HTT. Apigenin suppresses the VEGF-A/VEGFR2 pathway [176]. Apigenin possesses an anti-inflammatory effect [177]. Similarly, Withaferin-A reduces the levels of IL-1β, IL-6, and TNF-α. This shows their anti-inflammatory potential [206]. Curcumin and genistein modulate the expression levels of many miR - NAs [189–191]. Thus, apigenin, withaferin-A, curcumin, and genistein show mechanisms of action similar to gene therapy and stem cell therapy. The above findings make us hypothesize that the pro - posed formulation may establish itself as a stand-alone therapy. However, preclinical evaluation will predict the possibility based on the therapeutic outcome. Presently we have not come across any research that reflects the contraindication for these phytoconstituents in endo - metriosis. This enhances the possibility of being a stand- alone therapy. Even, adverse effects are very scarce which are reported above. However, clinical studies in postmen- opausal women have shown that genistein may produce gastrointestinal side effects [281]. Similarly, resveratrol is associated with ROS-mediated proteolysis and DNA damage [282]. However, this seems to be an advantage as PDT therapy of endometriosis depends on the pro - duction of ROS [280]. Thus, actual adverse effects of the formulation have to be determined to evaluate the safety profile. Prima facie the therapeutic implications may include the following: a decrease in the proliferation of EESC, invasion, vascularization, pain sensation, inflammation, gestational diabetes mellitus, and fetal growth restriction. There may be an increase in the fertility rate.

Several phytoconstituents have been found to effec - tively target the molecular mediators of endometriosis. Herbal formulations containing phytoconstituents such as apigenin, genistein, resveratrol, 5α-hydroxycostic acid, hydroxyisocostic acid, anthocyanins, quercetin, naringenin, kaempferol, withaferin-A, ursolic acid, shogaol, curcumin, demethoxycurcumin, capsaicin, ellagic acid, 6‐ paradol, 6‐ gingerol, carnosic acid, tuber - ostemonine-O, rosmarinic acid, luteolin, granatin-B, and licochalcone-A may be useful in the treatment of emdometriosis. This formulation may decrease the pro - liferation of EESCs, their invasion, vascularization, pain sensation, inflammation, gestational diabetes mellitus, Page 19 of 27 Paul et al. Middle East Fertility Society Journal (2025) 30:6 and fetal growth restriction. There may be an increase in the fertility rate also. This is due to their ability to regulate the expression of many molecular targets such as VEGF-A/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, IL-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, miRNA-155, miR-183, miR-223, MMP-1, MMP-2, MMP-3, MMP- 9, lncRNA-MEG3, lncRNA-H19, Ang-1 mRNA, Ang-2 mRNA, mRNA of urokinase plasminogen activator, mRNA expression and secretion of leptin, CD31, Tie- 2, MCP-1 mRNA and protein, HGF, Nrf2, HO1, Keap1, COX-2, PGE-2, MKNK1, and human DNA TOP3A. However, further clinical validation is required to determine the safety, compatibility, and therapeutic efficacy of this formulation. Abbreviations vWF Von Willebrand factor ADAMTS13 A disintegrin and metalloproteinase with thrombospondin motifs 13 COMT Catechol-O-methyltransferase COPD Chronic obstructive pulmonary disease AD Alzheimer’s disease HPV Human papillomavirus POD Pouch of Douglas rASRM Revised American Society for Reproductive Medicine EFI Endometriosis fertility index ART Assisted reproductive technology ER-α Estrogen receptor-alpha ER-β Estrogen receptor-beta IL-1 Interleukin-1 COX Cyclooxygenase PGE2 Prostaglandin-E2 SNP Single nucleotide polymorphism VEGF Vascular endothelial growth factor CD31 Cluster of differentiation 31 Tie2 TEK tyrosine kinase WISP-3 WNT-inducible signaling pathway protein-3 MAPK Mitogen-activated protein kinase HIF-1α Hypoxia-inducible factor 1-alpha ERK Extracellular signal-regulated kinase NF-kB Nuclear factor kappa B MMP-9 Metalloproteinase-9 GSTM1 Glutathione S-transferase mu 1 MKNK1 MAP kinase-interacting serine/threonine-protein kinase 1 TOP3A DNA topoisomerase III alpha EESC Ectopic endometrial stromal cells lncRNA Long non-coding RNA MEG3 Maternally expressed gene 3 miRNA MicroRNA

None. Authors’ contributions D.P ., R.A. and M.A.I wrote the main manuscript text and D.P . prepared Figs. 1–2. All authors reviewed the manuscript. Funding This work did not receive any funding. Data availability No datasets were generated or analysed during the current study. Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare no competing interests. Received: 26 September 2024 Accepted: 15 March 2025

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