{"paper_id":"5da13406-771b-4d21-90b2-9b8e3eea98d5","body_text":"Endometriosis, a prevalent benign condition, impacts\napproximately 10% of women in their reproductive years\n( 1 ). It is characterized by the presence of endometriallike tissue outside the uterus, which includes stromal\nfibroblasts, epithelial cells, nerves, immune cells, and\nvascular/perivascular cells. Patients with endometriosis\noften suffer from dysmenorrhea, dyspareunia, pain\nduring defecation, dysuria and chronic pelvic pain, as\nwell as infertility, which significantly reduces their\nquality of life. The selection of the treatment approach\nis determined by several factors including the patient's\nage at the time of diagnosis, the stage of the disease, the\nsymptoms experienced by the patient, their priorities and\nexpectations, plans for fertility, safety considerations,\noccurrence of potential side effects, tolerability, and cost\n( 2 ). Considering that the current endometriosis treatments\nare associated with recurrence of pain and disease despite\nthe treatment of the disease and have many side effects,\nit seems that non-hormonal treatments and compounds\nthat target angiogenic processes, oxidative stress, and\ninflammation may be particularly useful for loss of\nprogression of endometriotic lesions ( 3 ). The aim of this\nstudy is to review and evaluate non-hormonal treatments\nfor endometriosis, with a focus on key biological processes\nsuch as angiogenesis, oxidative stress, and inflammation.\nWhile several theories have been proposed as to\nhow endometriosis develops, the etiology of the disease\nprocess is still debated. The proliferation of endometrial\ncells and the induction of an inflammatory response are the common denominator of all the most prevalent ideas,\nwhich include coelomic metaplasia, stem cells, Sampson's\nhypothesis of retrograde menstruation, and lymphatic/\nhematogenous spread ( 4 ).\nBenign metastasis theory states that the cause of\nendometriosis lesions is lymphatic/hematogenous\ndissemination of endometrial tissue. In studies, it was\nfound that lymph flows from the body of the uterus into\nthe ovary, which supports the role of the lymphatic system\nin the development of ovarian endometriosis. In addition,\nit has been found that in 6-7% of lymphadenectomies,\nlymph nodes contain endometrial tissue ( 5 ). This finding\nhas also been shown in a model of induced endometriosis.\nHistological reports that show the presence of\nendometriosis lesions in places far from the uterus, such\nas bone, lung and brain, are considered strong evidence in\nsupport of the theory of benign metastasis ( 6 ).\nIn the treatment of endometriosis, control of pain symptoms and prevention of recurrence\nafter surgery in the framework of long-term treatment strategies should be considered as\nthe main goal, however, current treatment options for endometriosis are not satisfactory.\nPrimary treatment of endometriosis is limited to hormonal treatments ( 7 ). Existing drugs\n(eg, combined oral contraceptive pills, progestins and gonadotropinreleasing hormone\n(GnRH) analogs, oral antagonists, and letrozole) disrupt ovarian function and are not\ntherapeutically effective. Actually, there is a chance that using anti-estrogen\nmedications will have serious negative effects, such the patient developing osteoporosis\nand their depression getting worse. However, it has been demonstrated that a substantial\nrecurrence incidence follows surgical excision of endometriosis lesions ( 8 ). Therefore,\npatients with endometriosis urgently need non-hormonal treatments that increase the\nregression of endometriosis lesions without causing severe side effects and affecting\nfertility. On the other hand, although the cause of endometriosis is still debated, there\nis a general consensus that several biological processes such as angiogenesis and\nvasculogenesis, oxidative stress, and inflammation, contributes to its complex\npathophysiology. Accordingly, it seems that non-hormonal therapies and compounds that\nsimultaneously target these processes may be particularly suitable for the prevention and\neradication of endometriotic lesions. Selecting the most suitable protein targets for\npharmacological therapy of endometriosis requires an understanding of the key biochemical\nprocesses involved in its development. We go over a few of the key molecular pathways that\nlead to the development of illness below.\nLike other tumor cells, endometriotic lesions also need dense blood vessels and new blood\nsources to transport oxygen, nutrients, eliminate catabolites, and maintain fluid balance\nfor their creation, survival, and proliferation, and in fact, angiogenesis is not only\nimportant for the development of the disease, but also plays an important role in the\ndevelopment of endometriosis through the creation of a vascular network ( 9 ). This issue\nhas been confirmed by increasing the expression of angiogenic factors, especially in\nactive lesions. In addition, angiogenesis is essential for normal uterine function.\nResearch has indicated that the eutopic endometrium in women with endometriosis has the\npotential to produce angiogenic factors ( 10 ). These factors can cause the abnormal growth\nof invasive cells in various areas outside the uterus, such as the ovaries, pelvic\nperitoneum, intestine, and diaphragm. This growth occurs in a hormonal and immune\nenvironment that is favorable for the development of endometriosis. Vascular endothelial\ngrowth factor (VEGF), a key angiogenic factor, plays a significant role in promoting\nangiogenesis. This glycoprotein stimulates the growth and movement of endothelial cells,\nenhances vascular permeability, and contributes to the formation of new blood vessels in\nlesions and endometriosis tissue ( 11 ). Peritoneal macrophages and implanted tissue are\nresponsible for producing VEGF. Additionally, its concentration rises in peritoneal fluid,\nserum, ovarian endometrioma, and both eutopic and ectopic endometrium in individuals with\nendometriosis. Therefore, it can be concluded that the use of drugs that have the ability\nto inhibit angiogenesis can be a promising approach in the treatment of endometriosis\n( 12 ).\nOxidative stress refers to an imbalance between the productions of reactive oxygen\nspecies (ROS) and the availability of antioxidants. ROS is a by-product of cellular\nmetabolism, and when its production exceeds a certain level, it can cause damage to the\nstructure and function of cells. In fact, excessive ROS production is a major contributor\nto cell death. Interestingly, oxidative stress has been found to stimulate the\nproliferation of endometrial and tumor cells, suggesting that ROS acts as a second\nmessenger in cell proliferation ( 13 ,  14 ). The cause of the proliferative response observed\nin the follicular fluid (FF) of women with endometriosis was previously unknown. However,\nit has been discovered that the induction of oxidative stress in the FF is responsible for\nthis response. It is believed that the FF may transmit this oxidative stress into the\nperitoneal fluid after ovulation, which then leads to an increased proliferation of\nectopic endometrial cells. Numerous studies have examined the antioxidant balance of\noxidants in the blood, peritoneal fluid, FF, and tissue environment of endometriosis\npatients ( 15 ). The levels of ROS in the serum and FF of individuals with endometriosis are\nsignificantly higher compared to those in the control group. Biomarkers of lipid\noxidation, including conjugated diene/triene, malondialdehyde, and oxidized low-density\nlipoproteins, are elevated in both the peritoneal fluid and serum of endometriosis\npatients. Furthermore, several studies have demonstrated that individuals with\nendometriosis have lower concentrations of antioxidant components such as vitamin A,\nvitamin C, vitamin E, and superoxide dismutase (SOD) in their serum and FF ( 16 ). The study\nconducted by Nasiri et al. ( 3 ) revealed that women diagnosed with endometriosis exhibited\nelevated levels of lipid peroxides (LPO) and decreased levels of total antioxidant\ncapacity (TAC) in both their FF and blood serum, in comparison to women in the control\ngroup. These findings indicate that oxidative stress plays a significant role in the\nprogression of endometriosis, and suggest that the utilization of antioxidants could\npotentially ameliorate the symptoms associated with this condition.\nEndometriosis has many characteristics of an immune disorder. The development of\nendometriosis lesion along with the secretion of excess cytokines in the angiogenic\nmicroenvironment creates an external chemotactic gradient ( 17 ). The levels of macrophages\nand their secreted products, including growth factors, cytokines, and angiogenic factors,\nare altered in the peritoneal fluid of women with endometriosis. Research has shown an\nincrease in the expression of VEGF, and its receptors, as well as pro-inflammatory\ncytokines such as interleukin-6 (IL-6), IL-8, and IL-1 in these patients compared to those\nwithout the condition ( 18 ). Pro-inflammatory cytokines like IL-1 and tumor necrosis\nfactor-alpha (TNF-α) promote angiogenesis and are produced by macrophages in response to\ninflammatory stimuli ( 19 ). Research has shown that the activation of genes involved in\nangiogenesis and tissue remodeling, such as nuclear factor-κB (NF-κB), is responsible for\nthe development of endometriosis. TNF-α, an angiogenic cytokine, plays a role in promoting\nthe production of other cytokines and the proliferation of endometriotic stromal cells in\npatients with endometriosis ( 20 ). It seems that these pro-inflammatory cytokines and\nangiogenic factors contribute to the formation of ectopic lesions, leading to the\ndevelopment of endometriosis ( 21 ). In fact, the levels of inflammatory cytokines and\nangiogenesis factors are elevated in patients with endometriosis, and these levels are\ninfluenced by the presence of endometriosis, resulting in an increased number of ectopic\nlesions. Studies show that the incidence of immune disorders is significantly increased in\npatients with endometriosis, especially autoimmune diseases and celiac disease ( 22 ). In\ngeneral, it can be said that immunotherapy may be a promising approach and an effective\nmethod in the treatment of this disease.\nAccording to recent research, several hormonal medications, including selective\nprogesterone receptor modulators and aromatase inhibitors, have not proven to be effective\nin treating endometriosis ( 23 ). Consequently, it would appear that non-hormonal substances\nthat concurrently address oxidative stress, inflammation, and angiogenic processes would\nbe more appropriate for the avoidance and removal of endometriosis lesions. Based on the\nfindings of several research studies to date, non-hormonal therapies may be categorized\ninto three subgroups: natural substances, immune modulators, and anti-angiogenic medicines\n( 24 ).\nRapamycin is a widely used drug that has antifungal, immunosuppressive, and antitumor\nactivities. In a study, it was determined that rapamycin as an anti-angiogenic agent plays\na role in the treatment of endometriosis in a way that leads to the regression of\nendometriosis lesions with a significant reduction in the size of the lesions in a short\nperiod of 14 days. In fact, this study showed that this drug, by inhibiting angiogenesis,\nleads to a decrease in the density of small vessels and newly formed microvascular\nnetworks in endometriosis lesions, and it was found that treatment with rapamycin leads to\na decrease in the expression of VEGF, which is one of the strongest angiogenic growth\nfactors ( 25 ). As a result, rapamycin medication might provide a novel therapeutic strategy\nfor endometriosis' anti-angiogenic management. The use of drugs such as rapamycin, whose\nside effects are not fully understood, it is preferable to assess the likelihood of their\nefficacy using in silico approaches before to prescription to patients. Nowadays, it's\ncommon practice to employ in silico techniques to lessen the adverse effects of\nmedications and unidentified chemicals ( 26 ).\nXanthohumol, a prenylated flavonoid found in hops, has been identified as a potent\ncancer-inhibiting compound. It targets multiple cellular mechanisms, leading to decreased\nproliferation and increased apoptosis in various cancer cell lines. Furthermore,\nxanthohumol exhibits anti-inflammatory properties by inhibiting NFκB signaling and\nreducing the expression of inflammatory cytokines such as IL-1. Studies have also\ndemonstrated its ability to inhibit VEGF secretion in both acute and chronic myelogenous\nleukemia cell lines ( 27 ). This suggests that xanthohumol effectively targets the\nangiogenic process. Studies have shown that xanthohumol inhibits the angiogenesis process\nand leads to a significant reduction in the vascularization of endometriosis lesions. The\nRudzitis-Auth study showed that xanthohumol inhibited cell proliferation in microvessels\nof endometriosis lesions without inducing endothelial cell apoptosis, which may be due to\ndirect inhibition of VEGF signaling. On the other hand, xanthohumol is able to scavenge\nROS, including hydroxyl and peroxyl radicals. In addition, it reduces the expression of\nVEGF in endometrial cells by inhibiting oxidative stress. Furthermore, it has been shown\nthat xanthohumol may inhibit the proliferation and growth of endometriotic lesions by\ninhibiting Phosphoinositide 3-kinase (PI3-K) signaling in endometriotic lesions ( 28 ). It\nwas also found that xanthohumol may affect the secretory activity of glandular epithelium.\nIn addition, consistent with previous studies, it was found that the efficacy of\nxanthohumol treatment was not essentially dependent on the location of endometriosis\nlesions within the peritoneal cavity. In addition to the analysis of endometriosis\nlesions, the effect of xanthohumol treatment on the uterus and ovaries was investigated to\nassess whether xanthohumol may cause severe side effects in reproductive organs. This is\nnot unlikely, because these organs have high angiogenic and proliferative activity.\nInterestingly, it was found that the uterine horns and ovaries of both groups of animals\ntreated with xanthohumol and control animals showed normal histomorphology and no\nfunctional differences were observed in terms of angiogenesis and cell proliferation.\nThese results were consistent with the study of Hussong et al. ( 29 ) who reported that even\noral administration of xanthohumol at doses higher than 100 mg/kg body weight did not\ncause any adverse effects on fertility and embryo development in rats. These results show\nthat xanthohumol can be useful for the treatment of endometriosis by inhibiting the growth\nand angiogenesis of endometriosis lesions without affecting the reproductive organs.\nCalligonum comosum, known as Escanbil, has antioxidant, anti-inflammatory and anti-cancer\neffects ( 30 ). In the study of Kiani et al. ( 1 ), it was shown for the first time that\nCalligonum comosum is also effective in inhibiting angiogenesis and due to its functional\nprofile, it can be a promising option for the treatment of endometriosis. For the\n in vivo  tests, they employed this last Calligonum comosum complete\nextract (CCTE). It was demonstrated that in mice endometriosis lesions, this plant’s\nextract inhibits growth, cyst formation, angiogenesis, and immune cell infiltration ( 31 ).\nThis plant's potent chemicals work by blocking the enzymes lipoxygenase (LOX-5) and\ncyclooxygenase (COX-2). In fact, by preventing inflammation and angiogenesis, CCTE can\nactually mitigate the illness ( 1 ).\nResveratrol ( 3 ,  5 , 4ʹ-trihydroxy-trans-stilbene) is a naturally synthesized polyphenolic\ncompound found in some fruits such as grapes, berries and nuts. There are many studies\nshowing the anti-neoplastic, anti-inflammatory, antioxidant and anti-angiogenic effects of\nresveratrol ( 31 ). In an experimental model of endometriosis, the antiangiogenic and\nanti-inflammatory effect of resveratrol was confirmed by showing a decrease in serum\nlevels of VEGF and MCP1 in endometriosis implants. In addition, resveratrol inhibits the\nformation of new blood vessels by significantly reducing the expression of VEGF in a mouse\nmodel of endometriosis ( 32 ). Experimental evidence shows that resveratrol effectively\ninhibits inflammatory responses induced by Sirtuin 1 (SIRT1) pathway in endometrial\nstromal cells (ESCs). Recently, a study by Khodarahmian et al showed that resveratrol\nreduces the expression of VEGF and TNF-α as angiogenic and inflammatory markers ( 33 ).\nTherefore, based on these results and considering the pro-apoptotic, antiinflammatory,\nantioxidant and anti-angiogenic effects of resveratrol, this drug may be a suitable\ntreatment for endometriosis patients.\nCurcumin is the main polyphenol isolated from turmeric. Curcumin’s anti-tumor,\nanti-mutagenic, anti-metastatic, anti-inflammatory, antioxidant, anti-angiogenic, wound\nhealing, hypoglycemic, antimicrobial and hormoneregulating properties have been confirmed\nby numerous studies ( 34 ). Based on the results of a laboratory study, it seems that\ncurcumin leads to the improvement of folliculogenesis in endometriosis. In addition,\ncurcumin prevents the development and spread of endometriosis by reducing estrogen\nproduction ( 35 ). Many animal studies have reported a reduction in endometriotic implant\nsize or delayed growth after curcumin administration ( 36 ). Human studies have reported the\neffects of curcumin in downregulating the VEGF signaling pathway and reducing serum CA125\nand prostaglandins (PGE2) levels ( 37 ). Therefore, curcumin seems to have potential\nbenefits as a dietary supplement and pharmacological agent for the prevention or treatment\nof endometriosis.\nQuercetin, also known as 3, 3′, 4′, 5, 7-pentahydroxyflavone, is a flavonol that can be\nfound in various vegetables and fruits, including onions, cauliflower, lettuce, apple\nskin, and chili peppers. It has been found to possess properties that can inhibit cell\nproliferation and induce cell cycle arrest in endometriosis cells. Additionally, quercetin\nhas been observed to trigger apoptosis by generating reactive oxygen species, causing DNA\nfragmentation, and disrupting mitochondrial membrane potential ( 38 ). Furthermore, an\nanimal study has demonstrated its anti-estrogenic and progesteronic effects ( 39 ).\nTherefore, quercetin may have a beneficial impact on the healing and treatment of\nendometriosis.\nN-acetylcysteine (NAC), which is the acetylated form of the amino acid cysteine, is\nnaturally found in certain vegetables like onion and garlic. It has been found to have an\ninhibitory effect on the growth of cancer cells ( 40 ). Research conducted in laboratories\nhas shown that the mechanism of action of NAC does not involve causing cell death or\ninducing a specific toxic effect. Instead, it is related to the differentiation pathway,\nwhich includes activating specific molecular mechanisms that result in a change in the\nrate of cell proliferation. Ultimately, this leads to a decrease in cell proliferation and\na decrease in cell locomotory behavior. Additionally, NAC has anti-inflammatory properties\n( 41 ). Animal studies have demonstrated that NAC significantly reduces the average size of\nlesions, as well as the levels of TNF-α in the serum and peritoneum, and the levels of the\ninflammatory enzyme COX-2. This could potentially explain the observed decrease in the\ndimensions of endometriomas ( 42 ). In fact, reducing the expression of COX-2 decreases the\namount of estrogen in the ectopic endometrial tissue by reducing the production of PGE2,\nwhich is a potent stimulator of aromatase. Researchers reported a reduction in the size of\nendometrioma in women who took NAC and concluded that NAC can effectively help treat\nendometriosis and prevent its recurrence and the possible reason for that is the effect of\nNAC on cell signaling and the activity of proteins involved in proliferation. In another\nstudy, the combined effect of NAC, alpha lipoic acid and bromelain was a significant\nreduction of pain in women with endometriosis ( 43 ). In a human study recently conducted by\nAsgari et al. ( 44 ), it was determined for the first time that the addition of NAC to low\ndose contraceptive treatment has a similar effect in reducing the recurrence rate of\nendometrioma and pelvic pain compared to low dose contraceptives alone, and it was\nsuggested that in subsequent studies and in order to increase the effectiveness of this\ntreatment method, the duration of drug use should be increased.\nAlpha-lipoic acid (α-LA) is a substance that is naturally found in spinach, broccoli and\ntomatoes and is also synthesized in the human body. When α-LA is taken orally, it is\nabsorbed from the intestinal villi and converted in liver cells to dihydrolipoic acid\n(DHLA), a powerful antioxidant. In a study conducted in an experimental model of\nendometriosis, it was found that oxidative stress, endometrial implant volume and\nhistopathological scores were lower in the group treated with α-LA compared to the control\ngroup ( 2 ). Other studies have shown that regular use of α-LA significantly improves\nendometriosis-related pain symptoms such as dyspareunia, dysmenorrhea, and chronic pelvic\npain, as well as increases quality of life and sexual function ( 2 ,  45 ). α-LA can be a good\noption for the treatment of endometriosis, especially in patients who mainly suffer from\nendometriosis pain.\nVitamin C is a water-soluble vitamin that is naturally found in citrus fruits, tomatoes,\npotatoes, red and green peppers, kiwi, broccoli, and strawberries. Intravenous injection\nof vitamin C leads to the inhibition of endometriotic implant induction and facilitating\nthe regression of endometriotic implant volume, which is due to the anti-inflammatory and\nanti-angiogenic effects of vitamin C. Also, vitamin C significantly reduces the volume and\nweight of endometriosis cysts in a dosedependent manner ( 46 ). In an experimental model, in\nthe group receiving vitamin C, the volume of the endometriosis implant was significantly\nlower than the control group ( 47 ). Human studies on the effects of vitamin C on\nendometriosis are few, a randomized controlled trial showed that vitamin C led to an\nincrease in the level of vitamin C in FF, however, it had no effect on markers of\noxidative stress ( 48 ). Due to its antioxidant, anti-inflammatory and anti-angiogenic\neffects, vitamin C can be considered to prevent the growth of endometriotic implants,\nespecially in patients with high oxidative stress.\nVitamin E, which can be found in vegetable oils, nuts, seeds, fruits, and vegetables, is\ncomposed of tocopherols and tocotrienols. When taken orally, vitamin E is absorbed by the\nintestinal villi and transported to the liver through chylomicrons. Alpha-tocopherols are\ncarried into the bloodstream after binding to specific proteins. Alphatocopherol, also\nknown as vitamin E, helps prevent lipid peroxidation and oxidative stress ( 2 ). Research\nhas shown that patients with endometriosis tend to have lower levels of vitamin E ( 2 ,  49 ).\nIt appears that individuals with endometriosis have higher levels of lipid peroxidase and\nlower levels of selenium, SOD, and vitamin E compared to healthy individuals ( 2 ). Patients\nwith moderate to severe endometriosis have lower levels of vitamin E and glutathione\ncompared to those with minimal to mild endometriosis, suggesting that the reduction in the\nantioxidant system is related to the severity of the disease. It is reported by\ninvestigators that patients with endometriosis who received antioxidant therapy combined\nwith vitamin C and E experienced significant reductions in chronic pelvic pain,\ndysmenorrhea, dyspareunia, and inflammatory parameters IL-6 and MCP-1 in peritoneal fluid.\nAnother study showed that levels of malondialdehyde (MDA) and lipid hydroperoxides (LOOH),\nindicators of oxidative stress in plasma and peritoneal fluid, were significantly lower\nafter six months of treatment with vitamins C and E. Vitamin E has an antioxidant effect,\nparticularly on lipid peroxidation. However, it may be more effective to use a combination\nof vitamin E and vitamin C supplements to alleviate pain.\nVitamin D is a fat-soluble vitamin that is naturally found in fatty fish such as salmon,\ntuna, and mackerel, as well as in liver, egg yolk, and cheese. It is mainly present in the\nform of vitamin D3 and its metabolite 25(OH)D3. Vitamin D, also known as\n1,25-dihydroxyvitamin-D3, plays a crucial role in immune modulation and affects cell\ndifferentiation and proliferation. There is a connection between Vitamin D deficiency,\nendometriosis, and autoimmune diseases ( 50 ). Furthermore, the presence of vitamin D\nreceptors and vitamin D metabolizing enzymes has been observed in the ovaries and\nendometrium of both healthy women and those with endometriosis. These receptors and\nenzymes are also found in immune cells. This suggests that vitamin D plays a role in the\nlocal immune response within these tissues ( 51 ). Vitamin D has been shown to decrease\nlevels of both pro-inflammatory cytokines (such as TNF-α, IL-2, IL-6) and antiinflammatory\ncytokines [like transforming growth factorbeta (TGF-β), IL-4], indicating its potential to\nalleviate symptoms of chronic inflammatory and autoimmune conditions ( 52 ). Research on\nanimal models has shown that vitamin D supplementation leads to a decrease in IL-6 levels\nin peritoneal fluid ( 53 ). A recent study conducted on the status of vitamin D in patients\nwith endometriosis revealed that women diagnosed with endometriosis had lower levels of\nvitamin D compared to the control group. Furthermore, the study found a negative\ncorrelation between the severity of endometriosis and vitamin D levels ( 54 ).\nOmega-3\nPolyunsaturated fatty acids (PUFAs) are rich in\nomega-3 fatty acids (FAs). The anti-proliferative, antiangiogenic, anti-inflammatory and anti-apoptotic effects\nof omega-3 PUFAs have been demonstrated in several\nstudies ( 55 ). Fish oil contains an omega-3 polyunsaturated\nfatty acid called Eicosapentaenoic acid (EPA), which\nstops arachidonic acid from converting to PGE2 and\nleukotrienes (LTB4) ( 56 ). Animal studies have reported\na reduction in pain associated with endometriosis after\nomega-3 supplementation ( 57 ). In addition to improving\nsymptoms, PUFAs also play a role in preventing disease\npathogenesis ( 58 ). Also, adding fish oil to the diet of\nendometriosis models reduced the size of lesions caused\nby endometriosis ( 59 ).\nEGCG is a plant compound found especially in green tea. Epigallocatechin-3-gallate (EGCG)\nhas been shown to inhibit VEGF expression and estrogen-dependent activation and\nproliferation of endometrial cells  in vitro  ( 60 ). It also significantly\nreduces the number and volume of endometriotic implants, inhibits cell proliferation,\nreduces vascularity, and increases apoptosis ( 61 ). A study conducted on mouse models of\nendometriosis showed that EGCG significantly reduced the growth of endometrial implants\nand lesion size and weight, and inhibited angiogenesis and induced apoptosis in the lesion\n( 62 ). Another animal study reported that EGCG down-regulates the VEGF signaling pathway\nand down-regulates VEGF expression, thereby inhibiting angiogenesis in endometriotic\nimplants ( 63 ). There are no human studies on the effects of EGCG on endometriosis.\nAspirin (Asp) is a synthesized chemical compound that is one of the most effective drugs\nin treating fever, inflammation and pain in patients with very few side effects. In\naddition, it has been found that Asp has the ability to inhibit fibrogenesis, reduce the\nepithelialmesenchymal transition (EMT), reduce the capacity of cell migration/invasion,\nand delay apoptosis ( 64 ). In the study of Nasiri et al. ( 65 ), for the first time, the\neffect of Asp on the expression of inflammatory factors, proliferation, invasion, adhesion\nand migration capacity of eutopic ESCs (EuESCs) obtained from endometrial biopsy of\npatients with severe endometriosis (stage IV) was investigated in comparison to control\nESCs (CESCs). Asp, as an efficient drug for the treatment of several types of cancer,\nprobably acts through regulation of NF-κB signaling and simultaneous inhibition of\nproliferation and regulation of apoptosis ( 66 ). It has been found that Asp leads to the\ninhibition of NF-κB mainly by inhibiting the activity of IKK. It is a factor that\nseparates NF-κB from its inhibitory factor, IKB, and leads to NF-κB activation ( 67 ). This\nevidence indicates the effectiveness of Asp in controlling endometriosis.\nMetformin, which was discovered in 1922, is widely used as an anti-diabetic medication.\nRecent research has shown that diabetic patients treated with metformin have a lower risk\nof developing cancer compared to those taking other antidiabetic drugs. Additionally,\ncombining metformin with chemotherapy agents such as carboplatin, cisplatin, doxorubicin,\nand paclitaxel has been found to enhance the effectiveness of these drugs by increasing\ntheir cytotoxicity. Metformin has also been investigated as a potential treatment for\ncancer ( 68 ). Studies have demonstrated that metformin can reduce the migration and\nproliferation of ESCs in a time-dependent manner. It has been shown to decrease the\nexpression of VEGF, Hypoxia-inducible factor (HIF), MMP-2, and MMP-9, while increasing the\nexpression of TIMP in ECT-ESCs. These effects may be attributed to metformin's\nantiinflammatory properties, which can help mitigate the inflammatory processes associated\nwith endometriosis lesions. Inflammation in endometriosis can stimulate angiogenesis and\ncontribute to the progression of the condition through elevated VEGF levels ( 69 ). A study\ndemonstrated that the expression of angiogenic factors such as VEGF can be reduced by\nmetformin, leading to an improvement in sensitivity to progesterone through an increase in\nthe expression of the progesterone receptor ( 70 ). Yilmaz et al. ( 71 ) found that metformin\ntreatment resulted in a notable decrease in VEGF and MMP-9 levels, an increase in TIMP\nlevels, and regression of endometriotic implants. Clinical trial results on endometriosis\npatients indicated that metformin significantly reduced dysmenorrhea, pelvic pain, and\nserum VEGF levels ( 72 ). Based on its ability to lower inflammation, inhibit angiogenesis,\nand impede cell proliferation, it can be inferred that metformin holds potential as a\ntreatment for endometriosis.\nPentoxifylline (PTX), a methylxanthine with known hemorological activity, has been used\nfor many years in the treatment of peripheral vascular disease. Several studies show the\nanti-inflammatory, antioxidant and antiangiogenic effect of this drug ( 73 ). In an animal\nmodel, PTX is able to induce regression of endometriotic tissue without causing a\nhypoestrogenic state ( 74 ). In another animal study, it was found that pentoxifylline, in\naddition to reducing the number and size of endometriosis lesions, leads to a decrease in\nthe expression of the angiogenic factor VEGF-C and its receptor flk-1 ( 75 ). In another\nanimal study, Perello et al. ( 73 ) reported that PTX significantly reduced the number and\nsize of endometriosis lesions, decreased the expression of inflammatory cytokines (IL-1b,\nIL-6, and TNF-α) and increased the expression of the anti-inflammatory cytokine IL-10. In\naddition, it leads to a decrease in VEGF expression and angiogenesis. There are few\nrandomized, controlled trials in humans evaluating the efficacy of PTX after surgical\ntreatment of endometriosis ( 76 ). Therefore, it seems that this drug can potentially be\nused in new treatment methods for endometriosis. However, more human studies are needed.\nThe drug research and development (R&D) for\nendometriosis has been painfully slow ( 77 ). Nowadays,\nthe use of computational methods has been very effective\nin drug discovery for the treatment of multifactorial\ndiseases ( 78 ,  79 ). According to scattered studies in\nthe field of identifying effective drugs in the treatment\nof endometriosis, the use of in silico methods is very\neffective in increasing the speed and accuracy to discover\ndrugs in the treatment of this disease ( 80 ).\n\nConsidering that the current endometriosis treatments\nare associated with recurrence of pain and disease despite\nthe treatment of the disease and have many side effects,\nit seems that non-hormonal treatments and compounds\nthat target angiogenic processes, oxidative stress, and\ninflammation may be particularly useful for loss of\nprogression of endometriotic lesions.\nIt is important to note that studies in this field often\nhave limitations, such as experimental study design and\nlow sample size. In addition, one should keep in mind that\nthese drugs may have different mechanisms of actions,\nalso there are still questions and there is no consensus\nabout on dosing and recommendation guidelines. Using in\nsilico methods can help to choose more accurately FDAapproved drugs and herbal compounds for the treatment\nof endometriosis.","source_license":"CC0","license_restricted":false}