{"paper_id":"1dab7876-a59b-44f2-8019-442189896e7a","body_text":"The Mechanism and Treatment Research Progress of \nMetformin in Treating Endometriosis  \nFenxiu Cai1,2,a, Qianyu Wang1,2,b, Wenhong Hu2,c,* \n1Department of Gynecology, The Second Affiliated Hospital of Dali University, Kunming, Yunnan, \nChina \n2School of Clinical Medicine, Dali University, Dali, Yunnan, China \nacaixiufen0929@163.com, b1532058264@qq.com, c18687126600@163.com \n*Corresponding author \nKeywords: Endometriosis; Metformin; Mechanism; Side effects; Drug treatment \nAbstract: Endometriosis is a common disease in women of childbearing age, and its \nspecific pathogenesis is not yet clear. The clinical pharmacological treatment mainly \ninvolves the continuous use of progestins, GnRH analogs, danazol, aromatase inhibitors, \nand other drugs. However, some studies have shown that various medications have \nlimitations in their application for the treatment of endometriosis. Metformin is a widely \nused insulin sensitizer for treating type 2 diabetes. Due to its pleiotropic effects, metformin \nis now also applied in the treatment of endometriosis. It mainly works by activating the \nadenosine monophosphate-activated protein kinase (AMPK) signaling pathway, inhibiting \ninterleukin (IL)-1-mediated IL-8 secretion, and reducing the expression of the anti-\napoptotic gene Bcl-2. Metformin's use in treating endometriosis has a unique mechanism of \naction, without serious side effects, making it an effective anti-inflammatory and anti-\nproliferative drug. This article aims to explore the mechanism of action of metformin in \nendometriosis and the possibility of drug treatment. \n1.\n Introduction \nEndometriosis (EMT) is a common gynecological disease that mainly occurs in women of \nchildbearing age, typically between 25 and 45 years old. It affects approximately 10% of women of \nreproductive age globally, with the prevalence among infertile women reaching 20% to 50% [1]. The \nexact causes and pathogenesis of EMT are still not fully understood. Several theories exist \nregarding the pathogenesis of EMT, including the implantation theory (retrograde menstruation, \niatrogenic implantation, lymphatic and venous spread), the coelomic metaplasia theory, the \ninduction theory, as well as interactions at hormonal, genetic, immunological, and environmental \nlevels[2][3]. Traditional treatments for endometriosis m ainly include surgery and drug therapy. \nHowever, traditional drug therapy only provides temporary relief of symptoms, and the drugs are \noften expensive with many side effects[4]. Metformin, as an oral hypoglycemic medication, has been \nclinically practiced in China for over 30 years [5]. Recent studies have found that Metformin can \nsignificantly reduce the incidence of tumors in diabetic patients [6]. In the pathogenesis of \nendometriosis, the \"retrograde menstruation theory\" is the most prominent, which elucid ates the \nMEDS Clinical Medicine (2024) \nClausius Scientific Press, Canada\nDOI: 10.23977/medsc.2024.050325 \nISSN 2616-1907 Vol. 5 Num. 3\n166\n\nsimilarities between endometriosis and malignant tumors in certain aspects such as progressive and \ninvasive growth, estrogen-dependent growth, tendency for recurrence and metastasis [7]. \nEpidemiological and multiple clinical trial data indicate that long- term use of metformin has a \npreventive and adjuvant therapeutic effect on lung cancer, breast cancer, and gynecological \nmalignancies[8]. Therefore, this article analyzes the mechanism and current diagnosis and treatment \nstatus of metformin in endometriosis. \n2.\n The mechanism of metformin in endometriosis  \n2.1 Activating the adenosine monophosphate-activated protein kinase (AMPK) signaling \npathway reduces estrogen synthesis: inhibiting the expression of steroidogenic acute \nregulatory protein (StAR) and P450 aromatase mediated by prostaglandin E2 in ectopic \nendometrial stromal cells, thereby reducing estrogen synthesis[9,10] \nAMPK is a serine/threonine protein kinase that plays a crucial role in regulating cell metabolism, \ngrowth, and survival, serving as a primary enzyme in modulating cellular energy homeostasis [10]. \nMetformin can trigger the phosphorylation of mitogen -activated protein kinase (MEK)/extracellular \nsignal-regulated kinase (ERK) [9][11], thus activating the AMPK signaling pathway and inhibiting \nprostaglandin E2 (PGE2) in ectopic endometrial stromal cells. PGE2 stimulates the transcription of \nStAR by enhancing the binding of the cyclic adenosine monophosphate response element -binding \nprotein (CREB) and its co-activator CRTC2 to the StAR promoter region. This, in turn, activates the \nbinding site of the cyclic adenosine monophosphate response element (CRE), increases AMPK \nphosphorylation to prevent the nuclear translocation of CREB -regulated transcription coactivator 2 \n(CRTC2), and weakens the association between CREB and CRTC2 as a transcription complex [10]. \nPGE2 can induce the nuclear translocation of CRTC2 and enhance its association with CREB, \nforming a transcription complex that binds to the StAR promoter region. PGE2 can also mediate the \nexpression of P450scc, HDS3B2, and HSD17B1 [9], inhibit the interaction between CREB and its \nco-activator CRTC2, and prevent them from binding to the StAR promoter region. Research has \nshown that metformin treatment can disrupt the association between CRTC2 and CREB for 12 to 48 \nhours, without altering the baseline levels of these two proteins [9].\n Therefore, metformin alleviates \nendometriosis by triggering the AMPK signaling pathway, PGE2 -mediated expression of StAR and \nP450 aromatase, etc., to achieve reduction of estrogen synthesis. \n2.2 Metformin also reduces the secretion of interleukin (IL)-8 mediated by interleukin-1, \ndecreases aromatase activity, and inhibits the proliferation of ectopic endometrial cells. \nInflammatory responses play a significant role in the development and progression of \nendometriosis[12]. Studies have shown that metformin can inhibit inflammation [13]. IL -8 plays a \nsignificant regulatory role in the inflammatory process [14], and the levels of IL -8 in the peritoneal \nfluid of patients with endometriosis are elevated [15]. Metformin can inhibit the production of IL -8 \ninduced by IL-1β. According to a study by Takemura Y [13], human embryonic stem cells incubated \nwith metformin showed a statistically significant dose\n-dependent reduction in IL -8 production \ninduced by IL -1β. Metformin appears to exert anti -inflammatory effects by reducing the secretion \nof pro -inflammatory cytokines in specific cell types. It can inhibit the release of IL -8 in human \nadipose tissue [16] and suppress the release of IL -6 and IL -8 induced by IL -1β in human vascular \nendothelial cells. However, at the same dosage, metformin can inhibit the secretion of IL -8 in \nembryonic stem cells induced by IL -1β but does not inhibit the secretion of IL -8 in ectopic \nendometrial stromal cells[17]. As is well known, endometriosis is an estrogen-dependent disease, and \nthe local production of estrogen within endometriotic tissues is a significant factor in the \n167\n\npathogenesis. Research indicates[18] that abundant expression of aromatase can lead to an increase in \nlocal estrogen production in endometriotic tissues, suggesting that aromatase is responsible for local \nestrogen production. Aromatase inhibitors, by inhibiting the conversion of androstenedione to \nestrone, thereby suppressing follicle -stimulating hormone in granulosa cells, have also become one \nof the treatment options for endometriosis. This combined therapy primarily causes regression of \nendometrial implants in rodents through anti -estrogenic and anti -inflammatory effects, aiming to \nreduce the proliferation of ectopic endometrial cells. \n2.3 It can lower the expression of the anti-apoptotic gene Bcl-2, increase the expression of the \npro\n-apoptotic genes Bax and p53, restore the balance of the apoptotic regulatory system \nwithin the eutopic endometrial cells, thereby promoting cell apoptosis.  \nCell apoptosis is an important factor for the cyclical shedding and sustained stability of \nendometrial tissue, and it is precisely due to the increased anti -apoptotic activity of endometrial \ncells that ectopic endometrial tissue is able to implant outside the uterine cavity and survive [19]. The \nmost studied apoptotic regulatory proteins in EMT are Bcl -2, Bax, and P53. Bcl -2 is an inhibitor of \nthe intrinsic apoptotic pathway. Shan[20] found that activation of the ERK signaling pathway in EMT \nlesions can lead to Bcl -2 activation, thereby reducing EMT cell apoptosis and increasing cell \nsurvival. Lyu S and others [21] discovered that EMT patients exhibit significantly increased \nexpression of the anti-apoptotic gene Bcl-2 protein, while the expression of the pro -apoptotic genes \nBax and P53 is significantly lower compared to non -EMT individuals, resulting in an elevated Bcl -\n2/Bax ratio. The imbalance in the expression of the apoptotic regulatory proteins leads to a \nsignificantly lower apoptosis rate in endometrial cells of EMT patients compared to normal \nendometrial cells. This places them in a state resembling a special immunological function, where \nectopic endometrial cells cannot be cleared normally, leading to the formation of ectopic lesions and \nthe development of symptoms. However, metformin can reduce the expression of the anti -apoptotic \ngene Bcl-2, increase the expression of the pro -apoptotic genes Bax and p53, restore the balance of \nthe apoptotic regulatory system within eutopic endometrial cells, thereby promoting cell \napoptosis[22]. ELGENDY M's research [23] has found that metformin dephosphorylates protein \nphosphatase 2A (PP2A) to activate GSK-3β (glycogen synthase kinase-3 beta), reduces the levels of \nMCL-1 (a member of the Bcl -2 family), and induces apoptosis in tumor cells. Through research, \nZheng Z et al. [24] found that metformin increases the expression of the pro -apoptotic protein Bax, \nelevates the Bcl -2/Bax ratio. LISMH research [24] discovered that metformin upregulates P53, \nstimulates the p53 signaling pathway, reduces the protein kinase B (AKT)/mTOR (mammalian \ntarget of rapamycin)/eukaryotic translation initiation factor 4E -binding protein 1 signaling pathway \nto induce cell apoptosis and cell cycle arrest, thereby inhibiting tumor growth [26]. Li et al. [25] \nobserved that metformin decreases p53 expression levels, significantly induces apoptosis and cell \ndeath, and increases the phosphorylation of liver kinase B1 (LKB1), promoting p53 activation and \nAMPK, and inhibiting cell cycle progression[27].\n \n3. The application of metformin in the treatment of endometriosis \n3.1 Treatment of metformin combined with progestin \nDeferiprone is a synthetic progestin commonly used in clinics, which can effectively reduce the \nendocrine stimulation of the ovary in patients with endometriosis, prevent endometrial hyperplasia \nand carcinoma due to high estrogen, accelerate the contraction of ectopic endometrial tissues and at \nthe same time prevent new endometrial ectasia, and does not damage the normal endometrium of \nthe body while having this effect, and does not inhibit normal ovulation in patients after the use of \n168\n\nthe drug, which is especially suitable for patients with fertility requirements [28]. It is especially \nsuitable for patients with fertility requirements. Peng et al.'s study and analysis of 1709 cases using \ndienogest to treat patients with endometriosis showed that compared to progesterone, dienogest can \nsignificantly alleviate dysmenorrhea, increase the pregnancy rate, and reduce the risk of adverse \nevents, and that dienogest can lower the risks of endometriosis recurrence and elevated \ntransaminase levels compared to GnRH -a[29]. It can be seen that dienogest has relatively mild drug \nside effects in the treatment of endometriosis, with good drug safety and tolerability. However, \nconservative treatment of ovarian endometriotic cysts with oral dienogest requires a longer \ntreatment process. As scholars have found through research, it takes 17 months for ovarian \nendometriotic cysts to show significant shrinkage when treated with oral dienogest, and complete \ndisappearance of the cysts may take up to 40 months [30]. Therefore, it is quite possible that poor \nearly efficacy, prolonged treatment processes, and high costs may lead to decreased patient \ncompliance. In comparison to the singular drug effects, Cai Wenjuan et al. [31] found that the \ncombined use of dienogest with metformin yields better results. The two can work synergistically, \nnot only effectively improving the patient's symptoms and accelerating recovery, but also reducing \nthe recurrence rate and occurrence of adverse reactions, while also enhancing the inhibitory effect \non estrogen, effectively reducing the levels of P, FSH, and E2 in the body. \n3.2 Treatment of metformin combined with aromatase inhibitors \nUterine endometrial tissues of patients with endometriosis have relatively high expression of \naromatase, and the estrogen content can also increase significantly [32]. Aromatase inhibitors have a \nsignificant effect on accelerating apoptosis of endometrial cells and can also inhibit estrogen \nsynthesis. Aromatase inhibitors typically include steroidal and nonsteroidal types, commonly used \nin clinical practice such as letrozole, anastrozole, etc. Among them, letrozole is a nonsteroidal \naromatase inhibitor with very high selectivity and relatively strong specificity, showing significant \neffectiveness in the treatment of endometriosis. Some scholars have shown through clinical studies \nthat when letrozole is used alone to treat endometriosis for 3 months, over 50% of patients may \ndevelop functional ovarian cysts. Even after undergoing surgery for endometriosis followed by \nletrozole treatment for 2 months, about 24% of patients still experience functional ovarian cysts, \nalong with elevated FSH levels detected after 3 months of postoperative treatment [33]. Therefore, it \ncan be seen that the effect of using letrozole alone for patients with endometriosis is not very ideal, \nindicating that in practice, other drugs should be used in combination for adjuvant therapy. Some \nscholars have found through research that the combined treatment of metformin and letrozole for \nendometriosis can inhibit the secretion of androgens and improve clinical outcomes [34]. Researchers \nsuch as Tian Liang [35] found through their studies that the combined treatment of letrozole and \nmetformin resulted in a better overall efficacy and improvement in pain severity compared to the \ncontrol group using letrozole alone. The application of letrozole and metformin in combination for \nthe treatment of endometriosis has shown significant effectiveness. There are also clinical studies \nwith small sample sizes showing that the combination of metformin and letrozole for treating \nendometriosis is more effective in improving pain symptoms, reducing nodular lesions, and \nlowering the recurrence rate compared to using letrozole in combination with leuprorelin[22].\n \n4. Side effects of metformin \nWhile there are many benefits to using metformin, some of its side effects should not be \noverlooked. Some of the most common side effects of using metformin derivatives are \ngastrointestinal symptoms[36]. Due to long\n-term use leading to the accumulation of substances in the \nintestine, approximately 20 -30% of patients may experience mild to moderate illness [37]. In the \n169\n\nstudy conducted by Ma et al. [38], 44% of patients experience symptoms of diarrhea, while nausea is \nreported in as high as 40% of cases. For common side effects, starting with a low dose, gradually \nincreasing the dosage, taking immediate-release formulations with meals, or switching to extended -\nrelease formulations can help reduce gastrointestinal adverse reactions [5]. If chronic diarrhea \nprogresses to the point where hospitalization is needed, it can manifest as symptomatic electrolyte \nabnormalities such as hypocalcemia, hypokalemia, hypomagnesemia, and hypophosphatemia. Most \ngastrointestinal symptoms can be alleviated by supplementing with vitamin B12 [39]. The reason for \nthis is that long -term use of metformin can lead to poor absorption of vitamin B12 [40]. If patients \nsuddenly develop anemia and/or peripheral neuropathy, this cause should also be considered[41]. It is \nrecommended that patients with inadequate intake or absorption of vitamin B12 undergo annual \nmonitoring of vitamin B12 levels before and after starting metformin treatment, and if deficient, \nappropriate supplementation should be provided. It is worth noting that a very rare complication of \nmetformin is lactic acidosis, a life -threatening condition that can present with symptoms such as \narrhythmia, dizziness, difficulty breathing, and significant diarrhea [42]. This condition may be \ninduced by the accumulation of metformin in the body, although there is currently no definitive \nreport establishing a causal relationship. It is relatively common in patients with heart or lung \ndiseases, acute worsening of kidney function, or sepsis, but long -term use of metformin does not \nincrease the risk of lactic acidosis in patients with normal liver and kidney function12. The incidence \nof lactic acidosis with the appropriate use of metformin is not significantly different from other \nantidiabetic treatments[43].\n \n5. Conclusion \nThe foundation of treating endometriosis is the reduction of endogenous steroid hormone \nproduction[44]. However, the long-term use of individual drugs such as progestins, GnRH analogues, \ndanazol, and aromatase inhibitors has gradually revealed their limitations. This may be related to \nfactors such as their side effects, cost, delayed fertility, prolonged treatment duration, and high \nrecurrence rates after discontinuation [45]. Metformin is a widely available drug with a low price, \nhigh safety profile, and relatively mild side effects. Adjunct medications can accelerate recovery, \nshorten treatment duration, and save overall costs. In patients with endometriosis, the combination \ntreatment with metformin has been shown to alter the serum cytokine levels, increase the chance of \nconception, suggesting that metformin may have a beneficial role as an anti -endometriosis \nmedication[46]. However, there is relatively limited existing research on the consequences of using \nmetf\normin to treat endometriosis, and the results of these studies vary. Clinical trials are also scarce, \nand there is currently no clear evidence indicating its specific effect on endometrial mesenchymal \ntransition (EMT) in the treatment of endometriosis. As a result, the widespread use of metformin in \nthe clinical setting for treating endometriosis has yet to be established. Therefore, further research is \nneeded to elucidate the role of metformin as an anti-endometriosis medication. \nAuthor Contributions  \nF-X C was primarily responsible for literature retrieval and analysis, as well as drafting the \ninitial manuscript. Q-Y W coordinated and supervised the collection and analysis of literature. W -H \nH reviewed and revised the manuscript, conducting critical reviews of important intellectual \ncontent. All authors contributed to the conception and design of the study. 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