{"paper_id":"88ed4060-d25a-47dd-9598-85991f54bc09","body_text":"Shah et al. \nFuture Journal of Pharmaceutical Sciences           (2024) 10:35  \nhttps://doi.org/10.1186/s43094-024-00609-1\nREVIEW\nA comprehensive review comparing \nconventional versus traditional remedies \nin the treatment of endometriosis with futuristic \ninsights\nMansi Shah1, Bhavarth Dave2, Shivam Bhagat2, Hetansh Rao2, Avinash Khadela2 and Nisha Parikh3*   \nAbstract \nBackground A common condition known as endometriosis typically takes place in females in their reproductive \nage and develops generally in the endometrial lining of females. Chronically, endometriosis has been associated \nwith a reduction in the patient’s quality of life (QOL) which can have a hazardous impact on their social working \nand functionality. Owing to the involvement of hormones in the development of endometriosis, drugs having \nthe capability to modulate the hormonal concentrations, along with surgical techniques, have been designed to treat \nendometriosis.\nMain body There are certain drawbacks of the currently existing therapy for endometriosis which include the inabil-\nity to improve the quality of life of the patient, treatment failures and unresponsiveness from the patient, and adverse \neffects of the drugs such as weight gain, mood swings, vaginal dryness, etc. Herbal medicines have attracted \nthe attention of various researchers for the development of novel therapeutics against several gynecological disor-\nders, mainly endometriosis. Our present review summarizes the precise pathogenesis of endometriosis along with its \nconventional therapy and novel developments in herbal medicines wherein we have compiled data from 15 com-\npleted clinical trials (conventional therapy: 7, herbal therapy: 8). Additionally, we have included data from four pre-\nclinical studies on herbal medicine that showed promising results in treating endometriosis highlighting the neces-\nsity for clinical trials to yield more definitive findings. The number of clinical trials carried out to assess the response \nof herbs in endometriosis is limited which is why additional studies could provide beneficial concrete evidence \nin the effective treatment of endometriosis and ensure improved patient outcomes.\nConclusion Conventional therapies possess certain limitations to treat endometriosis due to which the attention \nof scientists has shifted toward herbal therapy due to its advantages such as improved safety and tolerability in treat-\ning endometriosis. However, additional clinical investigations into herbal therapy may prove to be fruitful in the dis-\ncovery of novel therapeutics to treat endometriosis effectively.\nKeywords Estrogen, Progesterone, Conventional therapy, Herbal therapy, Endometriosis, GnRH agonist\nOpen Access\n© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which \npermits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the \noriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or \nother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line \nto the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory \nregulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this \nlicence, visit http://creativecommons.org/licenses/by/4.0/.\nFuture Journal of\nPharmaceutical Sciences\n*Correspondence:\nNisha Parikh\nNisha.parikh@lmcp.ac.in\nFull list of author information is available at the end of the article\n\nPage 2 of 19Shah et al. Future Journal of Pharmaceutical Sciences           (2024) 10:35 \nBackground\nThe endometrium constitutes the deepest layer of the \nuterus located within the female reproductive system, \nand it is composed of luminal and glandular epithelial \ncells [1, 2]. Any damage to the endothelial layer may dis -\nrupt the process of implantation and may lead to endo -\nmetriosis (Fig. 1) [3–5].\nEndometriosis can be identified by the development \nof tissues similar to endometrial tissues that grow out -\nside of the uterine lining that can cause pain in the pelvic \nregion and on a chronic basis may also lead to infertility. \nIt usually occurs in females that are in their reproduc -\ntive age, i.e., 18–54 years [6]. Although the exact factors \nor mechanisms behind endometriosis are still unknown, \nseveral theories have been proposed as to how its lesions \narise [7]. Several symptoms arise due to endometriosis \nincluding intermenstrual bleeding, irregularity in menses \n(dysmenorrhea), dyschezia, dysuria, and also disruption \nin quality of life among patients which makes it a critical \ndisease that needs to be dealt with [7, 8].\nAccording to estimates, endometriosis usually is \nnoticed in females falling between 18 and 54 years of age \nFig. 1 An illustrative diagram representing the various factors causing endometriosis and the role of inflammation in its pathogenesis. Due \nto several factors including genetic, environmental, and lifestyle factors, dysfunction of the hypothalamic-pituitary axis (HPA-axis) takes place \nfollowing which the production of female reproductive hormones such as LH, FSH, Anti-mullein hormone (AMH), etc. becomes impaired leading \nto an imbalance ultimately resulting in the release of inflammatory markers due to initiation process of inflammation. This can lead to damage \nin the endometrial layer and result in the formation of endometrial lesions resulting in pelvic pain and enlargement of the endometrium causing \nEndometriosis\n\nPage 3 of 19\nShah et al. Future Journal of Pharmaceutical Sciences           (2024) 10:35 \n \nwith its proportion of incidences varying from 10 to 15% \n[9]. The development of this disease has been observed to \ntake place in up to 50% of women that have experienced \ninfertility along with 47% of adults that have undergone \nlaparoscopic procedures at some point in their life expe -\nriencing pelvic discomfort [7]. When the race-wise risk \nwas calculated to develop endometriosis, it was noted \nthat the Asian women population was at the highest risk \nof developing endometriosis, while black women were \nobserved to possess the highest possibility to develop \nendometriosis [10]. It has been observed that the preva -\nlence of endometriosis in developed countries such as \nthe USA, Russia, China, etc., was found to be 20% [11]. \nSimilarly, the incidence rate of endometriosis was found \nto range from 34 to 48% in developing countries such as \nIndia [12]. Hormonal imbalances and their alterations \ncan lead to elevations in the probability to develop endo -\nmetriosis. Along with these menstrual factors, the early \nage at which menstruation commences and reduced \nmenstrual period  may also influence the likelihood of \nendometriosis [13–15]. Furthermore, lifestyle factors \nsuch as caffeine and alcohol intake are also associated \nwith the development of endometriosis [16, 17]. Several \nfactors leading to endometriosis are highlighted in Fig. 2.\nThe conventional therapies for the management of \nendometriosis include hormonal agents (norethin -\ndrone, medroxyprogesterone acetate, cyproterone \nacetate, dienogest), contraceptive pills (estrogen–pro -\ngesterone, progestin), gonadotrophin-releasing hormone \n(GnRH) agonists (leuprolide, buserelin) and antagonists \n(cetrorelix, ganirelix), and  selective estrogen receptor \nmodulator (tamoxifen, raloxifene) [18]. Patients suffering \nfrom endometriosis are known to experience pain in their \npelvic region along with abdominal pain due to which \nthey are usually given non-steroidal anti-inflammatory \ndrugs (NSAIDs) to relieve them from their complaints of \npain and steroids to regulate inflammation occurring in \nthe endometrial region [19–21].\nThe majority of therapies designed to combat endome -\ntriosis are dependent on estrogen and other hormones as \nthey constitute a majority of the disease’s etiopathogen -\nesis [22]. However, there are certain limitations of con -\nventional therapy used in endometriosis such as risk of \nrecurrences, safety and efficacy issues, risk of develop -\nment of adverse events, etc. [23–25].\nDue to the toxic effects of synthetic drugs, more atten -\ntion has been shifted toward medicinal herbal drugs to \ncope with the harmful side effects of conventional ther -\napy in various gynecological disorders. Herbal drugs \nhave emerged as a more reliable source for the discov -\nery of novel therapeutic approaches for endometriosis \n[26]. They target several mechanisms associated with \nendometriosis such as inflammatory markers, estrogen \nreceptors, growth factors responsible for the angiogen -\nesis of endometrial tissues, etc. The herb Epigallocatechin \nGallate (EGCG) was shown to reduce inflammation by \nsuppressing the release of NF-κB  along with mitogen-\nactivated protein kinase 1 (MAPK-1) in the endometrial \nlesions  [27]. Similarly, Curcumin and Ginsenoside Rg3 \ncan inhibit the effects of vascular endothelial-derived \nFig. 2 Factors leading to endometriosis. Several factors may lead to endometriosis that include Genetic susceptibility towards particular genes, \nImmunological factors such as the stimulation of certain immune cells comprising Natural Killer cells, etc., Environmental factors such as exposure \nto some trigger chemicals and lastly the activation of inflammatory markers such as Interleukins (IL-1,3), NF-κβ, and TNF-α\n\nPage 4 of 19Shah et al. Future Journal of Pharmaceutical Sciences           (2024) 10:35 \ngrowth factor (VEGF) necessary for angiogenesis of the \nendometrial lining in rats suggesting their potency in \nendometriosis [28]. Furthermore, Curcumin, Ginseno -\nside Rg3, Resveratrol, Apegenin, and  β-Caryophyllene \ndecrease the levels of IL-6, IL-8, and NF-κB in human \nendometrial stromal cells. Also, Puerarin, Resveratrol, \nCurcumin, Ginsenoside Rg3, Genistein, and Herbal \ndecoction method have been shown to attach to estro -\ngenic receptors and compete with 17β-estradiol (E2), \nthereby inhibiting the production of estrogen. Their \nprobable mechanism in endometriosis is to suppress \nthe vascularization of the endometrial cells by targeting \nestrogen as it blocks the synthesis of estrogen through \nrepression of the expression of aromatase cytochrome \nP450 (p450arom)  in the endothelial stromal tissues as \nshown in Fig. 3 [29–32].\nThe present review compares conventional and herbal \ntherapy based on literature evidences with the objective \nto identify prospective novel targets in the treatment \nof endometriosis. A literature search was conducted \nthrough an electronic database (PubMed, Medline, \nClinicaltrials.gov, etc.) up to September 2023. The \nFig. 3 An illustration representing the various sites at which herbs act in lowering the progression of endometriosis. Several traditional herbs \npossess many properties through which they can influence the progression of endometriosis such as Anti-oxidative (Ginsenoside, Apigenin, \nβ-Caryophyllene), Anti-inflammatory (EGCG, Ginsenoside Rg3, Xanthohumol, Geinstein), Hormone regulatory effects (Puerin, Resveratrol, Genistein), \nand Anti-apoptotic effects (Ginsenoside). These herbs can work individually or in combination to treat the underlying causes of Endometriosis\n\nPage 5 of 19\nShah et al. Future Journal of Pharmaceutical Sciences           (2024) 10:35 \n \nfollowing key words were entered for search strategy: \nEndometriosis, Conventional therapy, GnRH agonist, \nEstrogens, Progestins, Selective estrogen receptor modu -\nlators (SERMs), Non-steroidal anti-inflammatory drugs \n(NSAIDs), Herbal therapy, Traditional medicine, Gen -\nistein, Curcumin, Ginsenoside Rg3, Herbal decoction \nmethod, Puerarin, Resveratrol, etc. Literature sources \nwere assessed based on this search strategy and included \ninto the present review. Additionally, it gives insights into \nthe various conventional therapy used for endometriosis \nalong with their limitations and whether herbal medicine \nhave any benefits over conventional therapies.\nMain Text\nConventional therapy for endometriosis\nEstrogen–progestins and progestins\nAlso termed combined hormonal contraceptives (CHCs), \nthey are given to the patients in the form of combined \npills containing both estrogen and progesterone to bal -\nance the levels of female reproductive hormones. These \npills are being administered to patients with endome -\ntriosis for a long time [33]. Both hormones possess their \nindividual properties in lowering the damaging effects \nof endometriosis on the female body. Estradiol has the \nunique characteristics of anti-apoptosis and anti-inflam -\nmatory properties which can lower the amount of  the \ninflammation process occurring at the endometrium, \nwhile progesterone also possesses anti-inflammatory \nproperties but promotes apoptosis. Estradiol has the \nunique characteristics of anti-apoptosis and anti-inflam -\nmatory properties which can lower the amount of  the \ninflammation process occurring at the endometrium \nwhile progesterone also possesses anti-inflammatory \nproperties but promotes apoptosis [34]. Moreover, they \nlessen or stop menstruation entirely, which limits the \nnumber of endometrial cells that reflux into the tubules. \nThese pills contain a higher level of progestin while hav -\ning a low level of estrogen. They are involved with regu -\nlarizing the menstrual cycle. As a result of this, it would \nlead to a delay in the inflammation process and oxida -\ntive stress occurring within the endometrial layer [35]. \nThere have been several investigations that have been \nconducted in this context, and it has been reported that \nabout two-thirds of the female population have benefit -\nted from estrogen–progestin therapy and their dysmen -\norrhea also got corrected [33, 36–38]. Certain examples \nof progesterone include medroxyprogesterone, norethis -\nterone acetate, desogestrel, etc. [39].\nGonadotrophin‑releasing hormone (GnRH) agonists \nand antagonists\nThe mechanism behind GnRH analogues is that they \ncause the pituitary gonadotrophs to be stimulated \nand further promote the release of follicle-stimulat -\ning hormone (FSH), luteinizing hormone (LH), etc., \nthereby maintaining the normal female reproductive \nsystem  function and the endometrial lining [40]. An \neffective strategy to combat endometriosis includes \nthe withdrawal of the hormone (estrogen) which can be \nprovided by administering GnRH agonist. However, a \nhigher estrogen withdrawal may result in unpredicted \nadverse events including bone density loss, altered men -\ntal status, and risk for cardiovascular disorders which \ncan lead to osteoporosis [33, 41]. Elagolix is a common \ndrug included within the category of GnRH agonists \nand is used for endometriosis and it has shown signifi -\ncant results under clinical investigations [42]. The utiliza-\ntion of GnRH antagonists in a similar manner to GnRH \nagonists has also been evaluated in endometriosis. On \nevaluation, it was observed that treatment with GnRH \nantagonists like Cetrorelix, Abarelix, and Ozarelix can \nensure the successful inhibition of gonadotrophins while \nalso maintaining the levels of estrogen in the body. Due \nto this, the adverse events noted with GnRH agonists can \nbe reduced along with the progression of the disease [41]. \nHence, endometriosis now has a new avenue for medical \ntreatment due to the administration of Cetrorelix which \nis an GnRH antagonist.\nProgestins\nAnother promising avenue for the treatment of endo -\nmetriosis includes therapy with progesterone-only pills \nwhich are available in the market in several dosage forms \nsuch as transdermal patches, oral pills, intrauterine \ndevices, etc. They have been associated with alleviation \nin pain and irregularity in menses along with limiting the \nsize of the endometrial lesion [43]. They may act through \nvarious mechanisms such as inhibiting angiogenesis \naround the endometrial lining, inhibiting aromatase \nenzyme, catalyzing anovulation, modulating estrogen \nreceptors, and decreasing the expression of 17β-HSD1 \n(hydroxysteroid dehydrogenase) [44]. Examples of pro -\ngestins include medroxyprogesterone acetate, norethin -\ndrone, cyproterone acetate, lynesterole, etc. [45, 46]\nSelective estrogen receptor modulators (SERMs) and selective \nprogesterone receptor modulators (SPRMs)\nThese agents can attach themselves to estrogen or pro -\ngesterone receptors and modulate their function result -\ning in modulating their signaling pathway. Due to this, \nthe menstrual cycle gets restored due to regained bal -\nance between the estrogen and progesterone hormone \nlevels. Certain examples of SERMs include tamoxifen, \nraloxifene, bazedoxifene, etc., while of SPRMs include \nmifepristone, asoprisnil, lonaprisan, etc. [43, 47, 48]. \nHowever, there is no hormonal therapy for endometriosis \n\nPage 6 of 19Shah et al. Future Journal of Pharmaceutical Sciences           (2024) 10:35 \nthat is free from adverse events and a therapy should be \ndesigned in such a way that it doesn’t influence the nor -\nmal menstrual cycle of the body in any way and sub -\nsequently leads to endometrial lesion size reduction \nthereby decreasing the inflammation process occurring \nwithin it.\nNon‑steroidal anti‑inflammatory drugs\nAs discussed above, inflammation is an important con -\nstituent in the development of endometriosis due to the \nrelease of prostaglandins and this ultimately leads to pain \nin the patient [49]. Due to this complaint of pain expe -\nrienced by the patients, NSAIDs can be prescribed as a \nsupplemental therapy to relieve the patients from their \npain symptoms [46]. Drugs such as mefenamic acid, nap -\nroxen sodium, ketoprofen, and ibuprofen at doses of 400 \nto 600 mg in the form of oral tablets for the duration of 6 \nto 9 months [19, 50].\nFigure  4 shows a brief timeline for the development \nof various drugs used as conventional therapies to treat \nendometriosis along with their mechanisms of action.\nShortcomings of conventional therapy in Endometriosis\nConventional therapy for endometriosis has been shown \nto possess certain drawbacks which include:\nTolerability issues\nThere have been instances wherein the current treat -\nment options for endometriosis (majorly hormonal \nagents) have not been successfully tolerated. Estrogen \nand progestins can be given in the form of combined oral \ncontraceptives (COCs) to balance the hormonal levels \nof the body. However, they are associated with several \nadverse events due to which their tolerability decreases \nin patients [24]. Certain examples of adverse events of \nestrogens include vaginal bleeding and itching, irregular \nmenstruation, menstrual bleeding, gastric disturbances, \nhot flushes, mood swings, etc. [33]. Almost all therapeu -\ntics of endometriosis have safety and tolerability issues \nwhich is why they need to be checked in patients before \ngiving it on a chronic basis [33]. Similar to estrogen, pro -\ngestins are also associated with adverse events such as \nhirsutism, acne, mood alterations, and weight gain [43].\nSafety and efficacy issues\nIn some studies, it has been found that when monother -\napy is given to patients suffering from endometriosis, \nthere has not been the achievement of successful thera -\npeutic outcomes. In an clinical investigation performed \nby Giudice et  al., they observed that monotherapy with \nRelugolix is not to be given for chronic use [25]. Addi -\ntionally, Barbara and colleagues evaluated the safety and \nefficacy of GnRH agonists in endometriosis and observed \nthat on a long-term basis, GnRH monotherapy can -\nnot be administered to endometriosis patients it was \nnot found to be safe for them due to the development \nof severe adverse events such as weight gain, hot flushes \nmood swings which were frequently noticed in patients \n[33]. In terms of oral progestins, conventional therapy \nhas been linked to the development of various major \nadverse events such as neoplasms, malignancy, endocrine \nabnormalities, mental and behavioral disorders, and \nFig. 4 A diagram representing the timeline for the development of therapeutics employed in endometriosis treatment. This figure shows a timely \ndevelopment of the conventional agents for endometriosis in a progressive manner. The conventional agents comprise Anti-androgens (Danazol), \nProgestins (Norethindrone acetate, Medroxyprogesterone acetate), GnRH antagonists (Elagolix), GnRH agonists (Gosrelin, Leuprolide, Nafrelin). The \nyear of authorization along with their mechanisms in endometriosis has been provided in the above figure\n\nPage 7 of 19\nShah et al. Future Journal of Pharmaceutical Sciences           (2024) 10:35 \n \nmany more. The SAE incidence rate per 10,000 women-\nyears was 3.67% in long-term oral progestin users (treat -\nment for more than 15 months) and 4.16% in short-term \nusers (therapy for less than 15  months) which is why \npatients receiving conventional therapies are more prone \nto develop adverse drug reactions (ADRs) [51]. Due to \nthe limited efficacy and safety of the conventional treat -\nments, the patient ultimately has to undergo surgical pro-\ncedures such as laparoscopy, hysterectomy, etc. [45, 52].\nCost issues\nTreating endometriosis poses a substantial economic \nburden on the patients with the costs of therapy. This is \nthe reason why an emphasis must be made on the cost \nof the therapy given in endometriosis [53]. In a study \ncarried out by Soliman et al. wherein they evaluated the \ntotal direct costs and incremental costs between endo -\nmetriosis patient and non-endometriosis control groups, \nthey found a significant difference in both and concluded \nthat there is a significant incremental cost to be paid in \nendometriosis treatment as high as $10,002 and $2132 \nfor direct and indirect incremental costs [54]. Also, the \nadverse events incurred during the course of endometri -\nosis and due to its treatment, such as pelvic pain, infer -\ntility, irregular menses, and mood swings add up to the \nincremental cost that the patient has to pay to deal with \nthese complications [55].\nRisk of recurrences\nThe greatest risk that the currently available treatments \npose is the risk of recurrence of the disease due to the \nlimited efficacy of the drugs. In most cases, the rea -\nson behind this recurrence is the presence of residual \nlesions or from de novo cells [23]. It was observed that \nthe recurrence rates of endometriosis were 40–50% at a \n5-year interval and 21–23% at the end of 2 years. In addi -\ntion to this, the precise risk factors leading to the recur -\nrence of endometriosis have not been identified yet [56]. \nRecurrence of endometriosis has also been observed in \npost-operative patients who have undergone surgical \nprocedures for endometriosis [56]. Thus, it is necessary \nto control the recurrences of endometriosis to ensure \nbetter therapeutic outcomes in patients.\nClinical trial data of conventional therapy in endometriosis\nCompleted clinical trials\nA list of completed clinical studies and trials for endome-\ntriosis patients and their findings are provided in Table 1. \nCertain examples of landmark clinical trials assessing the \npotency of conventional therapy in endometriosis are \ngiven below.\nIn a Phase-I randomized, multicentric trial performed \nto assess the efficacy and safety of Aromatase inhibitors \n(Anastrozole) and Progestin against Placebo in patients \nsuffering from Endometriosis, 309 participants were \nrecruited (NCT02203331). They were divided into four \ncohorts, (a) participants receiving Progestin (Levonorg -\nestrel), (b) participants receiving Anastrozole in com -\nbination with levonorgestrel, (c) participants receiving \nleuprolide, and (d) participants receiving Placebo for the \nduration of 12 weeks. It was observed that all the drugs \nled to an improvement in the mean duration of endo -\nmetriosis-associated pelvic pain (EAPP) which led to a \nreduction in the days that patient presented with pelvic \npain [57].\nIn a similar Phase III study involving 815 participants, \nthe potency of Elagolix was determined in patients suf -\nfering from Moderate to Severe endometriosis induced \npain. The participants were divided into three cohorts: \n(a) patients receiving Elagolix 150  mg QD for a dura -\ntion of 6 months, (b) patients receiving Elagolix 200 mg \n4 times in a day for 6 months, and (c) patients receiving \nPlacebo drug for a 6-month duration. It was observed \nafter the treatment duration that Elagolix both lower and \nhigher dose resulted in improvements in endometriosis-\nassociated pelvic pain; however, adverse events such as \nhot flushes, increased serum lipid levels, increase in bone \nmineral density (BMD) was observed. Therefore, it was \nconcluded that conventional therapy, although effective \nled to the development of adverse events in patients of \nendometriosis [42].\nSuspended or terminated clinical trials\nThere have been certain instances wherein patients suf -\nfering from endometriosis were administered conven -\ntional therapy led to the termination or suspension of \nthe clinical trial due to certain complications occurring \ndue to the conventional agents. An example of such \ntrial includes a study in which 50 participants were \nenrolled who were clinically diagnosed with endome -\ntriosis and were divided into two groups: (a) receiving \nDienogest 2  mg per day and (b) receiving Levonorg -\nestrel (0.10  mg per day) in combination with ethinyl \nestradiol (0.02  mg per day) [62] are progestins which \nreduce endometrial lining thickness thus decreasing the \nchance of bleeding in patients of endometriosis [63]. \nThe outcomes measured included the change in size of \nthe endometrial lesions from their baseline observed \nvia ultrasound within a time duration of 1 year. It was \nobserved that Busrelin acetate which is a GnRH agonist \nwas equally effective in treating endometriosis as Dien -\nogest which is why these 2 drugs were given optionally \nto the patients. A significant improvement in the symp -\ntoms experienced by the patients and their pain score \nwas observed with patients that were administered Die -\nnogest. It also led to lower reduction in bone mineral \n\nPage 8 of 19Shah et al. Future Journal of Pharmaceutical Sciences           (2024) 10:35 \nTable 1 A table showing the various completed clinical trials for conventional therapy in endometriosis\nPhase Study design No of participants Eligibility criteria Arms of the study Study findings Inference Study\nPhase IV A randomized, par-\nallel, open-label \nstudy to determine \nwhether endometrial \nimplantation markers \npredict embryo transfer \nfertilization outcomes \nin vitro in subjects \nalready administered \nleuprolide acetate\n37 participants Infertility patients, diag-\nnosis of endometriosis \npatients, patients who \nhave regular menses, \nnormal ovarian reserve \ntesting\nIntervention: Leuprolide \nacetate in depot suspen-\nsion 3.75 mg intramuscu-\nlar every 28 days\nThe study found \nthat there were no sig-\nnificant differences \nfor outcomes such \nas rate of fertilization, \nstimulation of gonado-\ntrophin hormones, etc. \nA high rate of fertiliza-\ntion rates was observed \nin the group of patients \nwho were administered \nGnRH regimen which \nled to a larger fre-\nquency of implantations \nwithin them\nIt was concluded \nfrom this study \nthat GnRH agonist \nadministration in endo-\nmetriosis can lead \nto an increase in the rates \nof pregnancies in com-\nparison to the conven-\ntional ovarian stimulation \ntechniques\nSurrey et al. [58]\nPhase II A randomized parallel-\nassignment study \nto observe the effi-\ncacy of hormonal \ntherapy in combination \nwith GnRH agonist \nin patients suffering \nfrom endometriosis\n53 participants Women aged \n13–22 years, body weight \nbetween 18 and 30 kg/\nm2, surgical diagnosis \nof endometriosis, willing \nto comply with study \nrequirements\nIntervention: Norethin-\ndrone acetate 5 mg \norally + Conjugated \nequine estrogens \n0.625 mg orally\nControl: Norethindrone \nacetate 5 mg + placebo \ncapsule 1 pill daily\nAt 12 months, \nthe intervention group \nincreased the bone \nmineral density (BMD) \nand the overall mineral \ncontent of the body, \nwhile the control group \ndid not show these \noutcomes. Quality-of-life \nassessments showed \ngreater improvements \nin physical functioning \nwith the interventional \ngroup. There were no sig-\nnificant adverse events \nwere reported\nAdd-back therapy \nwith norethindrone \nacetate led to preser-\nvation of the skeletal \nhealth in endometriosis \npatients, the combina-\ntion of norethindrone \nacetate and conjugated \nequine estrogens being \nled to higher elevations \nin the BMD of the body. \nThe therapy was safe \nand effective, with no tol-\nerability issues\nDiVasta et al. [59]\nPhase II A randomized, parallel-\nassignment pilot study \nto determine the effect \nof dopamine receptor \nagonist therapy for pain \nrelief in women suffering \nfrom endometriosis\n10 participants Women with confirmed \ncase of endome-\ntriosis, age between 15 \nand 40 years\nIntervention 1: \nCabergoline (0.5 mg \nPO two times a week \nfor 6 months duration)\nIntervention 2: Norethin-\ndrone acetate (5 mg po \ndaily for 6 months)\nIt was observed from this \nstudy that many \nsubjects taking caber-\ngoline experienced \na decrease in pain scores \nand improvement in pain \ncomplaints compared \nto subjects treated \nwith Norethindrone \nacetate. Cabergoline \nwas also well tolerated \nby the patients\nIt was concluded \nthat Cabergoline could \nbe a safe and effective \ntherapeutic alternative \nfor chronic pain in endo-\nmetriosis resistant \nto standard care, accord-\ning to a pilot study. \nLarger randomized trials \nare needed to confirm \nthese findings\nDiVasta et al. [60]\n\nPage 9 of 19\nShah et al. Future Journal of Pharmaceutical Sciences           (2024) 10:35 \n \nTable 1 (continued)\nPhase Study design No of participants Eligibility criteria Arms of the study Study findings Inference Study\nPhase not applicable A prospective, rand-\nomized, parallel-assign-\nment clinical trial to study \nthe effect of administra-\ntion of GnRH agonist \nbefore in vitro fertilization \nto observe fertilization \nrate and pregnancy rate \nin endometriosis patients\n180 participants Patients with infertility, \nendometriosis stage 1\nIntervention: Leupro-\nlide (single injection \nof 3.75 mg every 28 days)\nProcedure: In vitro fertili-\nzation (IVF)\nThe use of GnRH agonist \nresulted in a decrease \nin Follicular fluid \ncytokines in women \ncompared to those \nwho did not receive \nthis regimen. However, \nno significant improve-\nment took place in terms \nof embryo quality, rate \nof implantation, or rate \nof pregnancy\nLow follicular fluid \ncytokine levels \nalong with high rates \nof implantations \nwere noticed in sub-\njects receiving GnRH \nagonist for the dura-\ntion of 3 months, \nwith no significant \ndifference in pregnancy \nand implantation rate\nKaponis et al. [61]\n\nPage 10 of 19Shah et al. Future Journal of Pharmaceutical Sciences           (2024) 10:35 \ndensity (BMD) as compared to Busrelin acetate. How -\never, compared to Busrelin acetate, a higher instance of \ngenital bleeding and hot flushes within these patients \nwas noticed with Dienogest highlighting its concern. \nThis was the reason due to which this trial had to be \nsuspended to avoid complications in these patients \n[62]. Due to the safety concerns occurring in conven -\ntional agents, it leads to negative therapeutic effects \nand it has been proposed that they be monitored care -\nfully during treatment and if they pose any risk to the \npatients, the trial should be terminated immediately. \nAlso, novel drugs which are safer and more tolerable by \nthe patients are required to prevent complications from \noccurring in them.\nHerbal therapy for endometriosis\nEpigallocatechin Gallate (EGCG)\nEpigallocatechin-3-gallate (EGCG) is the main constitu -\nent of green tea due to which it can display its potency \nin cancer and endometriosis [64]. This herb has already \nbeen shown to possess anticancer and anti-oxidative \nproperties. However, its effects in endometriosis were \nalso evaluated by several researchers in endometriosis. \nIt was shown to reduce inflammation by suppressing \nthe release of NF-κB  along with mitogen-activated pro -\ntein kinase 1 (MAPK-1) in the endometrial lesions [55]. \nHowever, sufficient investigations have not been carried \nout as of yet to underline the exact mechanisms of EGCG \nthrough which it can cure endometriosis. The preclini -\ncal testing of EGCG in endometriosis was done by Ricci \nand co-workers in which they observed that treatment \nwith EGCG inhibited the development of endometrial \nlesions along with decreasing the size of their lesions. It \nwas able to modulate cellular proliferation, decrease the \nblood circulation to and from the endometrial lesions, \nand enhance the process of apoptosis [65].\nCurcumin\nIt is the active ingredient of commonly occurring tur -\nmeric which has anti-inflammatory, anti-oxidative, and \nanti-proliferative properties [26, 66]. It can also block \nthe actions of vascular endothelial-derived growth fac -\ntor (VEGF) within the endometrial cells of the rats sug -\ngesting its effects as anti-angiogenetic agents as VEGF \nis crucial for endometrial blood vessels to grow further \nand proliferate [58]. Furthermore, it is able to decrease \nthe levels of IL-6, IL-8, and NF-κB in human endometrial \nstromal cells (Fig.  4). Hence due to all these beneficial \nproperties, it has been suggested that curcumin may also \nbe employed as a potential therapeutic agent for endo -\nmetriosis [26].\nGinsenoside Rg3\nThis is a Chinese traditional herb and is the active com -\nponent of ginseng which originates from the plant genus \nPanax. Preclinical findings have revealed the ability of \nthis herb in reducing the endometrial lesion size in rats \n[67]. Its main actions include anti-oxidative and anti-\ninflammatory activities [26, 59]. In addition to this, this \nherb can also repress the angiogenesis process by inhib -\niting the VEGF-mediated  formation of blood vessels \nsuggesting its efficacy in reducing endometriosis [60]. \nFurthermore, a study carried out by Huang et  al. found \nthat Ginsenoside Rg3 reduced inflammation by repres -\nsion of NF-κB and TNF-α in ectopic endometrial cells \nand also modulated apoptosis by regulating the expres -\nsion of caspase 3 and inhibiting VEGF-mediated angio -\ngenesis [68].\nPuerarin\nIt is the major active ingredient of Gegen which is \nextracted from the Chinese medical herb Radix puerariae \nand falls in the category of phytoestrogens but possesses \na weak estrogenic effect. They have sown to attach to \nestrogenic receptors and compete with 17β-estradiol (E2) \nthereby inhibiting the production of estrogen (Fig.  4). \nIts probable mechanism in endometriosis is its ability to \nsuppress the vascularization of the endometrial cells by \nestrogen as it blocks the synthesis of estrogen through \nrepression of the expression of aromatase cytochrome \nP450 (p450arom) in the endothelial stromal tissues \n[62–65]. When preclinical analysis was carried out, it \nsuggested that it could influence and inhibit the inflam -\nmatory microenvironment of the endometrial tissue in \nrats [32].\nResveratrol\nResveratrol is also a phytoestrogen that is derived from \ngrapes, wine, peanuts, etc. It has been identified to act \nagainst the progression of endometriosis due to its effects \nof anti-inflammation, via the repression of prostaglandin \nsynthesis along with the modulation of apoptosis [69]. It \nhas the ability to influence the estrogenic receptors (ER1 \nand 2) and has a mixed mechanism of action i.e., agonist \nand antagonist [67]. In addition to this, it has also been \nshown to regulate various pathways associated with cel -\nlular maturation and death such as MAPK, protein kinase \nB (Akt), protein kinase C, and peroxisome proliferator \nactivated receptor-gamma (PPAR-ϒ) [70–72].\nApigenin\nApigenin belongs to the category of flavonoids and is \nfound in parsley, celery, oranges, wheat sources, etc. It \npossesses, anti-inflammatory, anti-proliferative, and \n\nPage 11 of 19\nShah et al. Future Journal of Pharmaceutical Sciences           (2024) 10:35 \n \nanti-oxidant properties [73, 74]. Suou et  al. in a study \nto undermine the effects of apigenin in endometriosis \nobserved that it reduced inflammation via suppress -\ning protein expression and regulating the levels of IL-8 \nand TNF-α (Fig.  4) [75]. Recently conducted studies \nalso revealed its effect in acting through binding with \nthe progesterone receptors (PR) behaving as a probable \nphyto-progestin [76]. It was also shown to correct endo -\nmetriosis symptoms such as pelvic pain, dysmenorrhea, \ninfertility, etc. [77].\nβ‑Caryophyllene\nIt belongs to the category of sesquiterpenes and is the \nactive ingredient of essential oils which are derived from \nspices and food plants and is an effective anti-inflamma -\ntory herb in  vivo and was found to correct endometrial \nsymptoms and infertility in adult rats [78, 79]. It was \nshown to mediate the inflammatory response by regu -\nlating their markers such as IL-1β, TNF-α, and toll-like \nreceptors-4 (TLR-4) and angiogenesis by VEGF regula -\ntion. Recent findings also suggest its ability to block the \ngeneration of ROS through the MAPK pathway [74, 80].\nGenistein\nIt is an iso-flavonoid which is extracted from soy. It has \nstrong Phyto-estrogenic actions and has been demon -\nstrated both in vivo and in vitro and has been indicated \nin the treatment for endometriosis [81]. Genistein was \nshown to limit the progression of endometrial carcinoma \nin adult women as it regulated the process of angiogen -\nesis within the endometrium and apoptosis [82]. Addi -\ntionally, it can modulate the estrogenic receptors (ER) to \nregulate the release of estrogen and the process of angio -\ngenesis occurring due to it. Furthermore, it can regulate \ninflammation by mediating the release of IL-6 and TNF-α \n[81].\nXanthohumol\nIt is the active ingredient of Humulus lupulus L. and pos-\nsesses a variety of actions including anti-angiogenetic, \nanti-inflammatory, and anti-proliferative effects. Inflam -\nmatory mediators such as NK-κβ, IL-1, Akt etc. can be \nregulated due to this herb [74, 83].\nHerbal decoction method\nThese methods are commonly employed in China to \ntreat a variety of gynecological disorders such as endo -\nmetriosis since 1983 [84]. Certain examples of these \nmethods include Qu Yi Kang (QYK), Yi Wei San (YWS), \nXiaochaihu decoction (XCHD), Huoxue Xiaoyi (HX), \nand Xuefu Zhuyu (XZD) decoction methods based on \ntheir inventors [84]. Investigations into this have shown \nthat XZD may relieve the symptoms of endometriosis, \nsuch as dysmenorrhea and ectopic lesions, and improve \nthe issues of infertility in women and has resulted in \ngreater efficacy of about 90% in the past times [84, 85]. \nFurthermore, XCHD has been shown to reduce the lev -\nels of estradiol (E2) levels, aromatase enzymes and also \nmodulate the inflammatory mediator synthesis through \nthe blockade of the COX-2 enzyme [85]. Other methods \nof decoction include Cai Shi Nei Yi Fang, Neiyi Zhitong, \nHuazhuo Jiedu Huoxue, and Juan Tong Yin etc.[86].\nIn a study carried out by Ding et  al. involving 80 \npatients wherein they compared the effects of Chinese \ntraditional medicine and hormonal therapy (12.5  mg \nmifepristone orally each day) for Endometriosis. They \nobserved that Chinese traditional medicine had a greater \npregnancy rate (52.5%, 21/40) than hormonal therapy \n(37.5%, 15/40) within a 12-month period of follow-up \nand equivalent therapeutic effect to hormonal therapy \nsuggesting a better potency of herbal therapy. Moreover, \nthere were no SAE’s associated with herbal therapy and \nthe results of renal and hepatic profile parameters proved \nthat herbal therapy was well tolerated by all the patients \n[87]. This proves the long-standing efficacy as well as \nsafety of herbal medicine to treat Endometriosis.\nAdditionally, Zhao et  al. carried out a study in which \nthey compared the effects of Chinese herbal medicine \nand western medicine by the means of a randomized \ncontrolled trial in 208 patients (106 in Chinese herbal \nmedicine group and 102 in the western medicine group). \nPatients in the western medicine group were treated \nwith a GnRH agonist or gestrinone, whereas patients in \nthe Chinese medicine group were treated with agents \nincluding Modified Guifu Decoction, Radix Aconiti lat -\neralis Preparata, Ramulus Cinnamomi, Radix Linderae, \nRhizoma Sparganii, Rhizoma Curcumae, Spina Gledit -\nsia, Radix Salviae Miltiorrhizae, etc. For the patients in \nthe Chinese medicine group, the mean time following \nsurgery to achieve the first pregnancy was significantly \nshorter than for the patients in the Western medicine \ngroup (t = -2.09; P = 0.04). A statistically significant dif -\nference existed between the 2 groups in terms of safety \nobserved as after the treatment follow-up period, the \nwestern medicine group had increased ADRs such as \nfever, sweating, colpoxerosis, hypaphrodisia, weight gain, \ninsomnia, irregular bleeding, headache, acne, and bone \npain, while the patients in the Chinese medicine group \nonly complained of occasional stomach pain that was \nimmediately lowered after modifying the herbal remedies \nand dosages (83.3% vs. 9.4%, P < 0.01) [88].\nHerbal combination therapies were associated with \nimproving pregnancy rates, reducing adverse events and \ninhibiting the growth of endometrial tissues in addition \nto decreasing inflammation in patients. Therefore, com -\nbination therapy comprising of certain herbs may prove \n\nPage 12 of 19Shah et al. Future Journal of Pharmaceutical Sciences           (2024) 10:35 \nto be beneficial in treating Endometriosis compared to \nconventional therapies. Furthermore, they have shown \nimprovements in sub-populations of endometriosis \npatients including infertility patients, pre-menopausal \nsyndromes, menstrual cycle irregularities, autoimmune \ndisorders, etc. in terms of better hormonal balance res -\ntorations, ovulation induction, lowering inflammation \nproving their efficacy. The major herbal agents discussed \nin the present review such as curcumin, EGCG, Gen -\nistein, β-Caryophyllene, etc., have shown limited adverse \nevents in comparison with conventional therapy in terms \nof gastric disturbances including diarrhea, stomach \nupset, gastric irritation, etc. which can be easily managed \nwith supportive treatment thereby enhancing their safety \nprofile. In addition to this, their low cost of therapy adds \nto their benefit in treating Endometriosis.\nHerbal therapy has evolved over the recent times due \nto their offered advantages in the studies discussed above \nand other factors such as low cost, ease of convenience \nof preparing, reduced side effects and increased bioavail -\nability. However, several additional investigations and \nclinical trials need to be conducted to evaluate efficacy \nand safety of different combinations of herbal therapies \nin Endometriosis which may also lead to the discovery of \nnovel therapeutics to combat the disease effectively.\nPreclinical and clinical trial data of Herbal novel therapy \nin endometriosis\nThe current ongoing preclinical trials in which the inves -\ntigations into the effects of herbal medicine to treat endo-\nmetriosis are carried out are highlighted in Table 2.\nPreclinical trials\nCompleted clinical trials\nThere are a relatively limited number of clinical studies \ncarried out to evaluate the safety as well as efficacy of \nherbal medicine against endometriosis. Phase-I rand -\nomized, placebo-controlled trial was carried out in 185 \nparticipants to gain idea on the potency of green tea \nextract in endometriosis in which the effects of green \ntea or Epigallocatechin-3-gallate  were compared with a \nplacebo in order to assess its response. The investigators \nfound that green tea extract displayed anti-angiogenetic, \nanti-fibrotic, and anti-proliferative properties which led \nto beneficial outcomes in lowering the progression of \nendometriosis and was tolerable by the patients suggest -\ning its importance [91].\nSimilarly, a relatively same type of clinical trial was \nperformed to evaluate the potency of garlic in endome -\ntriosis. A total of 120 participants were recruited and one \ncohort was administered garlic tablets, while the other \nwas given a placebo after which the response toward \ntherapy was observed. It was noted that the patients that \nwere receiving garlic therapy showed improvements in \npain and statistical tests also showed its significance \nwhich concluded that herbal therapy can provide symp -\ntomatic relief also in addition to preventing the course of \nprogression of endometriosis [92].\nOngoing clinical trials\nTable 3 enlists the various investigations that are pres -\nently ongoing to investigate the effects of herbal therapy \nin endometriosis.\nFuture prospects and opportunities\nUp till now, the treatments under existence only aim to \nregulate the hormonal levels in the body and provide \nrelief from symptoms of endometriosis such as pain, \ndryness, infertility, etc. However, no specific treatments \nare available that can cure endometriosis completely \nor reduce its course of progression into its more severe \nforms. They only aim to suppress ovulation or alter the \nlevels of hormones such as estrogen and progesterone in \nthe body. Thus, there is a need to develop individualized \nregimens pertaining to specific patients to lower the inci -\ndences and recurrences of endometriosis [93]. Therefore, \nherbal medicines can prove to be a means to develop \nnovel therapeutics to be given to endometriosis patients \nas many drugs have shown potent effects in decreasing \nthe size of endometrial lesions and reducing inflamma -\ntion within them [81]. Herbal drugs are pleiotropic agents \nmeaning they have multiple mechanisms of actions such \nas anti-oxidative anti-inflammatory, anti-angiogenetic, \nestrogen-modulating, analgesic, etc., which could resolve \npelvic pain complaints of the patient along with lower -\ning endometrial inflammation by blocking the release of \ninflammatory markers and protection from ROS species. \nBy this, they can act as curative as well as symptomatic \nrelief-providing agents [94]. Also, the improved safety \nand tolerability profile along with reduced cost of therapy \nmakes them beneficial candidates over the conventionally \navailable drugs presently in the market [84, 95]. Further-\nmore, recent data suggests that medicinal cannabis as a \ndietary intervention may have effects in treating Endo -\nmetriosis as it acts through various mechanisms such as \nsuppressing inflammation, alleviating bloating, and act -\ning as a painkiller. However, it has not fully been studied \nand additional research into this can be fruitful [96, 97]. \nHerbal therapy can also be used to induce pregnancy in \nan individual who cannot conceive due to endometrio -\nsis and can be utilized as a safer approach compared to \nconventionally existing drugs with almost no harm to \nthe individual or the fetus [98]. Only further and larger \nnumber of studies need to be conducted in a similar \nmanner to evaluate the extent of the benefit that herbal \ntherapy provides or reducing the likelihood of developing \n\nPage 13 of 19\nShah et al. Future Journal of Pharmaceutical Sciences           (2024) 10:35 \n \nTable 2 A table showing the animal preclinical trials conducted to evaluate the potency of herbal medicine in endometriosis\nSr. No Study objectives Study design Arms of the study Study findings Study\n1 A study in order to find the association \nbetween the Ginsenoside Rg3 effect \non endometrial growth and the PI3K/\nAkt/mTOR signaling pathway modulated \nby VEGFR-2\nThe rats were allocated on the basis \nof randomization into 5 groups which \nwere treated with ginsenoside Rg3 \nand sacrificed 21 days post drug treat-\nment. Measurement of the endometrial \nvolume was carried out and the inhibi-\ntory rate was calculated. Serum estradiol \n(E2) and progesterone (P) levels were \nanalyzed by Electrochemiluminescence \nImmunoassay (ECLI). Using immunohisto-\nchemical techniques, the protein expres-\nsion of VEGF and VEGFR-2 was evaluated \nwithin the endometrium\nIntervention 1: Ginsenoside Rg3 (5 mg/\nkgBW/d)\nIntervention 2: Ginsenoside Rg3 (10 mg/\nkgBW/d)\nIntervention 3: Gestrinone group \n(0.5 mg/kgBW/d)\nIntervention 4: Control group (10 mL/kg \nBW/d of 0.5% Carboxymethyl cellulose \nsodium) CMC-Na\nIntervention 5: Ovariectomized group \n(10 mL/kgBW/d of 0.5%CMC-Na)\nIt was observed that a dose-dependent \nsuppression of endometrium size in rats \nin comparison to control group occurred. \nA down-regulation of the expression \nof VEGF and VEGFR-2 was also noticed \nin Ginsenoside Rg3 group\nCao et al. [67]\n2 A study to evaluate the effect of EGCG \nin mice-model of endometriosis\nThe potential for EGCG as an anti-angio-\ngenesis agent was investigated in mice \nsuffering from endometriosis. Trans-\nplantation of endometrium was done \nin mice and they were divided into 3 \ngroups to receive treatment for 4 weeks. \nEndometrial growth was measured \nthrough non-invasive in vivo imaging \n(IVIS). Post-treatment, the bioavailability, \nanti-oxidative and anti-angiogenesis \neffects were measured\nIntervention 1: Dulbecco phosphate \nbuffered saline\nIntervention 2: Vitamin E (20 mg/kg)\nIntervention 3: EGCG (50 mg/kg)\nA significant reduction in the endometrial \nlesion size was observed in the group \ntreated with EGCG from 2nd to 4th \nweek of drug treatment. However, they \nfailed to show effect on Ovarian follicles \nand uterine endometrial glands\nXu et al. [89]\n3 A study to investigate the potency \nof puerarin in endometriosis (EMT) model \nrats and to find the probable mechanisms \nof action\nThe animals were allocated into 5 groups \nand endometriosis was induced surgically \nby auto-transplantation of endometrial \ntissues. Serum estradiol (E2) and prosta-\nglandin E2 (PGE2) levels were analyzed \nand the dose of administration was calcu-\nlated. Genes and proteins of the endome-\ntrial tissues were analyzed by polymerase \nchain reaction (PCR) and immunohis-\ntochemistry (IHC). Based on the results, \nappropriate inferences were made\nPuerarin and Raloxifene (RLX) both mixed \nwith CMC prorata after which the animals \nwere allocated into five groups were \nrespectively administered drug treatment \nfor 4 weeks\nIntervention 1: low-dose group (0.1% \nCMC and 5 mg/kg puerarin)\nIntervention 2: 0.1% CMC and 20 mg/kg \npuerarin)\nIntervention 3: 0.1% CMC and 80 mg/kg \npuerarin)\nIntervention 4: positive control group \n(Raloxifene hydrochloride) RLX 10 mg/kg\nIntervention 5: Control group (CMC)\nIt was observed that Puerarin reduced \nthe concentrations of E2 and PGE2 \nand also hindered the maturation \nof endometrium tissues by inhibiting \nthe expression of aromatase cytochrome \nP450 (p450arom) and cyclooxygenase-2 \n(COX-2). Also, it modulated the metabo-\nlism of E2 by controlling the expression \nof the 17β-hydroxysteroid-2 (17β-hsd-2) \nenzyme of the endometrial tissues\nSurrey et al. [58]\n\nPage 14 of 19Shah et al. Future Journal of Pharmaceutical Sciences           (2024) 10:35 \nTable 2 (continued)\nSr. No Study objectives Study design Arms of the study Study findings Study\n4 A clinical study to assess the effect \nof β-caryophyllene on endometriosis \nalong with fertility status in adult female \nrats along with their roles in reproduction\nFragments of endometrium were \nimplanted in the peritoneal cavity \nof the animals to induce endometriosis \nwithin them. Their growth was measured \nfrom baseline and after 4 weeks. Alloca-\ntion was carried out of the animals into 2 \ngroups and they were given drug therapy \nfor a duration of 21 days\nIntervention: β-caryophyllene (10 mg/kg \nor 30 mg/kg)\nControl: Vehicle\nIt was observed that β-Caryophyllene \nwas able to hinder the maturation \nof endometriotic tissues 52.5% in rats \ncompared with controls whereas \nβ-caryophyllene led to apoptosis \nin the epithelium of the endometrial \nlesions\nAbbas et al. [90]\n\nPage 15 of 19\nShah et al. Future Journal of Pharmaceutical Sciences           (2024) 10:35 \n \nTable 3 Currently ongoing clinical studies for the evaluation of herbal therapy in endometriosis\nNCT number, current phase Study design Eligibility criteria Arms of the study Primary endpoints\nNCT04493476, Phase II A double-blind, prospective \nand placebo-regulated clinical trial \nto assess the response of combination \ntherapy of Chinese herbal medicine \nand curcumin to lower the symptoms \nof endometriosis\nWomen having a confirmed \ndiagnosis of endometriosis, women \naged 18–45 years (reproductive \nage), no allergy to the ingredients \nof the intervention or the control\nIntervention: Daily dietary dosing \nof Chinese medicine and curcumin \ngiven in the form of 800 mg capsules\nControl: Placebo (Invo capsules \ngiven in daily dosing)\nThe overall benefit in the symptoms \nof the disease\nNCT03016039 A randomized, parallel assignment \nstudy of curcumin supplementation \nfor endometriosis\nAge above 18, patient with a diag-\nnosis of pelvic inflammatory disease/\nTubo ovarian abscess, surgical wound \ninfection, endometritis\nIntervention: Curcumin supplementa-\ntion\nChange in the Levels of C-reactive \nprotein, change in the levels of white \nblood cells\nNCT03875261, Phase II A randomized, single-group assign-\nment study to examine the response \nof the effect of Cannabinoid (CBD) \non pain experienced by endometrio-\nsis patients\nWomen falling in the age group of 18 \nand 40, having a confirmed diagnosis \nof endometriosis with clinical inves-\ntigations, suffering from symptoms \nof pain, dysmenorrhea, etc.\nIntervention: Participants adminis-\ntered cannabinoid derivates dosing \nbetween 1 and 12 puffs. Each puff \ncontained 2–7 mg of delta-9-tetrahy-\ndrocannabinoland 2–5 mg of can-\nnabidiol\nPressure threshold in hypogastrium \nthat induces pain\nNCT02676713, Phase II A randomized, prospective, multi-\ncentric study to evaluate the efficacy \nof Decoction (Chinese herbal medi-\ncine to treat infertility) in endome-\ntriosis\nWomen having a clinical diagnosis \nof endometriosis, endometriosis fertil-\nity index (EFI) score greater than 4 \npoints, firstly undergoing laparo-\nscopic surgery, the female of repro-\nductive age (18–45 years)\nIntervention: Decoction (Bupleurum \n10 g, Cyperus 10 g, Salvia miltiorrhiza \n20 g, Red peony 10 g, etc.)\nPlacebo: Combination of maltodex-\ntrin, lactose, edible pigment, and taste \nmasking agent\nPregnancy rate to an extent of six \nmenstrual cycles\nNCT04150406, Current phase \nnot given\nA multicentric, randomized clinical \ntrial to evaluate the potency of Flexo-\nfytol in endometriosis\nWomen of reproductive age \n(18–51 years), diagnosed with endo-\nmetriosis, moderate to severe pelvic \npain\nIntervention: Flexofytol (Curcumin \n42 mg 2 capsules administered \nfor 4 months)\nControl: Placebo\nAlteration in the baseline pain score\nNCT number not given A randomized, multicentric clinical \ntrial to evaluate the effect of Ashoka-\nrishta, Ashwagandha Churna, \nand Praval Pishti in patients suffering \nfrom menopausal syndrome\nFemales of age 40–55 years, suffer-\ning from amenorrhea for a period \nof greater than 12 months, were will-\ning to comply with the study require-\nments, providing written consent \nto be included in the study\nIntervention: Ashokarishta (25 mL \ndaily), Ashwagandha (3 g twice daily \nwith milk), Praval Pishti (250 mg twice \ndaily)\nControl: Placebo\nImprovement in the Menopausal rating \nscale (MRS), Incidences of adverse \nevents (AEs)\n\nPage 16 of 19Shah et al. Future Journal of Pharmaceutical Sciences           (2024) 10:35 \nendometriosis and curing it completely. Herbal therapy \ntrials were limited in number, while trials for conven -\ntional therapy were found to be widely available. There -\nfore, when the results of trials for herbal therapy become \navailable, they will strengthen the point discussed in this \nmanuscript regarding the comparison of safety and effi -\ncacy of conventional and herbal medicine.\nConclusion\nThe currently existing conventional therapies are only \naimed at inhibiting the hormonal parameters of the \npatient and providing symptomatic relief from symp -\ntoms such as pelvic pain, vaginal dryness, etc., but can -\nnot completely cure the disease. Conventional therapy \nalso possesses several other limitations such as increased \ncost of therapy, risk of recurrence of endometriosis, lim -\nited safety and efficacy profile, and tolerability issues. \nOn the other hand, herbal therapies extracted from \nnatural sources have shown promising effects in delay -\ning the course of endometriosis progression and have \nbetter effects compared to conventional therapy along \nwith improved tolerability and almost no adverse events \nto the patients making them a perfect candidate for the \ntreatment of endometriosis concerning to efficacy, safety, \nand tolerability. The comprehensive studies data indicate \nthat conventional therapy results in unsatisfactory thera -\npeutic outcomes, disease recurrence, and an increase in \nthe development of ADRs, whereas herbal combination \ntherapy acts through multiple mechanisms, resulting \nin better clinical therapeutic outcomes and less ADRs, \nhighlighting their benefit in terms of efficacy and safety \nin treating endometriosis. However, the number of pre -\nclinical and clinical trials investigations into this context \nis limited which is why additional studies are crucial to \nidentify the potency of herbal drugs treating endometrio-\nsis effectively.\nAbbreviations\n17β-HSD1  17-Beta hydroxysteroid dehydrogenase\nADRs  Adverse drug reactions\nAEs  Adverse events\nAkt  Protein kinase B\nAMH  Anti-mullein hormone\nBMD  Bone mineral density\nBPA  Bisphenol-A\nCBD  Cannabinoid\nCHCs  Combined hormonal contraceptives\nCMC-Na  Carboxymethyl cellulose sodium\nCOCs  Combined oral contraceptives\nCRP  C-reactive protein\nE2  17β-Estradiol\nECLI  Electrochemiluminescence Immunoassay\nEFI  Endometriosis fertility index\nEGCG   Epigallocatechin Gallate\nEMT  Endometriosis model rats\nER1 and ER2  Estrogenic receptors 1 and 2\nFSH  Follicle-stimulating hormone\nGnRH  Gonadotrophin-releasing hormone\nHPA  Hypothalamic-pituitary axis\nHX  Huoxue Xiaoyi\nIHC  Immunohistochemistry\nIL  Interleukin\nIVF  In vitro fertilization\nIVIS  Non-invasive in vivo imaging\nLH  Luteinizing hormone\nMAPK-1  Mitogen-activated protein kinase-1\nMRS  Menopausal rating scale\nNF-κβ  Nuclear factor-kappa beta\nNSAIDs  Non-steroidal anti-inflammatory drugs\nP450arom  Aromatase cytochrome P450\nPCR  Polymerase chain reaction\nPGE2  Prostaglandin E2\nPKC  Protein kinase C\nPPAR-ϒ  Peroxisome proliferator activated receptor-gamma\nPR  Progesterone receptors\nQOL  Quality of life\nQYK  Qu Yi Kang\nRLX  Raloxifene hydrochloride\nSAE  Serious adverse events\nSERMs  Selective estrogen receptor modulators\nSPRMs  Selective progesterone receptor modulators\nTLR-4  Toll-like receptors-4\nTNF-α  Tumor necrosis factor-alpha\nUSA  United States of America\nVEGF  Vascular endothelial-derived growth factor\nXCHD  Xiaochaihu decoction\nXZD  Xuefu Zhuyu\nYWS  Yi Wei San\nAcknowledgements\nThe authors are grateful to Prof. Gaurang B. Shah, Department of Pharmacol-\nogy, L. M. College of Pharmacy, Ahmedabad, Gujarat, India, for kind support \nand guidance in manuscript preparation. The authors also extend their \nappreciation to the L. M. College of Pharmacy, Ahmedabad, India, for provid-\ning continuous library and resource support throughout the literature survey \nand data collection.\nDisclosure\nThe authors have no financial or non-financial interest to disclose. All the \ninvestigators take responsibility for the integrity of the data and the accuracy \nof the data analysis. All data from clinical trials of the use of herbal therapy \ntoward the treatment of endometriosis (https:// clini caltr ials. gov/).\nAuthor contributions\nBD, SB, HR and MS contributed to manuscript first draft preparation and \nsubsequent editing, literature and data collection, data analysis, figures and \ndiagram conception as well as designing and writing the manuscript. AK \nand NP contributed to topic conception, design of content and skeleton, \nmanuscript draft review and editing, figures and diagram conception, overall \nmonitoring, and guidance throughout the study duration. All authors have \nread and approved the final manuscript.\nFunding\nThis review did not receive any specific grant from funding agencies in the \npublic, commercial, or not-for-profit sectors.\nAvailability of data and materials\nThe datasets generated during and/or analyzed during the current study are \navailable from the corresponding author upon reasonable request.\nDeclarations\nEthics approval and consent to participate\nNot applicable.\nConsent for publication\nThe authors declare no conflict of interest.\n\nPage 17 of 19\nShah et al. Future Journal of Pharmaceutical Sciences           (2024) 10:35 \n \nCompeting interests\nThe authors declare that they have no competing interests.\nAuthor details\n1 Gujarat Technological University, Ahmedabad, Gujarat, India. 2 Department \nof Pharmacology, L. M. College of Pharmacy, Opp. Gujarat University, Navrang-\npura, Ahmedabad, Gujarat 380009, India. 3 Department of Pharmaceutical \nChemistry and Quality Assurance, L. M. College of Pharmacy, Opp. Gujarat \nUniversity, Navrangpura, Ahmedabad, Gujarat 380009, India. \nReceived: 5 November 2023   Accepted: 26 February 2024\nReferences\n 1. Maenhoudt N, De Moor A, Vankelecom H (2022) Modeling endometrium \nbiology and disease. J Pers Med 12(7):1048\n 2. Marquardt RM, Kim TH, Shin J-H, Jeong J-W (2019) Progesterone and \nestrogen signaling in the endometrium: What goes wrong in endome-\ntriosis? Int J Mol Sci 20(15):3822\n 3. Cha J, Sun X, Dey SK (2012) Mechanisms of implantation: strategies for \nsuccessful pregnancy. Nat Med 18(12):1754–1767. https:// doi. org/ 10. \n1038/ nm. 3012\n 4. Vasquez YM, DeMayo FJ (2013) Role of nuclear receptors in blastocyst \nimplantation. Semin Cell Dev Biol 24(10):724–735. https:// doi. org/ 10. \n1016/j. semcdb. 2013. 08. 004\n 5. Lee JY, Lee M, Lee SK (2011) Role of endometrial immune cells in implan-\ntation. Clin Exp Reprod Med 38(3):119–125. https:// doi. org/ 10. 5653/ cerm. \n2011. 38.3. 119\n 6. Chauhan S, More A, Chauhan V, Kathane A (2022) Endometriosis: a review \nof clinical diagnosis, treatment, and pathogenesis. Cureus 14(9):e28864. \nhttps:// doi. org/ 10. 7759/ cureus. 28864\n 7. Parasar P , Ozcan P , Terry KL (2017) Endometriosis: epidemiology, diagnosis \nand clinical management. Curr Obstet Gynecol Rep 6(1):34–41. https:// \ndoi. org/ 10. 1007/ s13669- 017- 0187-1\n 8. Sinaii N, Plumb K, Cotton L, Lambert A, Kennedy S, Zondervan K, Stratton \nP (2008) Differences in characteristics among 1,000 women with endo-\nmetriosis based on extent of disease. Fertil Steril 89(3):538–545. https:// \ndoi. org/ 10. 1016/j. fertn stert. 2007. 03. 069\n 9. Giudice LC, Kao LC (2004) Endometriosis. Lancet (Lond Engl) \n364(9447):1789–1799. https:// doi. org/ 10. 1016/ s0140- 6736(04) 17403-5\n 10. Smolarz B, Szyłło K, Romanowicz H (2021) Endometriosis: epidemiology, \nclassification, pathogenesis, treatment and genetics (review of literature). \nInt J Mol Sci 22(19):10554\n 11. Menakaya UA (2015) Managing endometriosis in Sub-Saharan Africa: \nemerging concepts and new techniques. Afr J Reprod Health 19(2):13–16\n 12. Rajeswari M, Ramanidevi T, Kadalmani B (2016) Cohort study of endome-\ntriosis in south Indian district. Int J Reprod Contracept Obstet Gynecol \n5:3884–3885. https:// doi. org/ 10. 18203/ 2320- 1770. ijrco g2016 3858\n 13. Missmer SA, Hankinson SE, Spiegelman D, Barbieri RL, Marshall LM, \nHunter DJ (2004) Incidence of laparoscopically confirmed endometriosis \nby demographic, anthropometric, and lifestyle factors. Am J Epidemiol \n160(8):784–796. https:// doi. org/ 10. 1093/ aje/ kwh275\n 14. Darrow SL, Vena JE, Batt RE, Zielezny MA, Michalek AM, Selman S (1993) \nMenstrual cycle characteristics and the risk of endometriosis. Epidemiol-\nogy 4(2):135–142. https:// doi. org/ 10. 1097/ 00001 648- 19930 3000- 00009\n 15. Sangi-Haghpeykar H, Poindexter AN 3rd (1995) Epidemiology of endo-\nmetriosis among parous women. Obstet Gynecol 85(6):983–992. https:// \ndoi. org/ 10. 1016/ 0029- 7844(95) 00074-2\n 16. Parazzini F, Chiaffarino F, Surace M, Chatenoud L, Cipriani S, Chiantera V, \nBenzi G, Fedele L (2004) Selected food intake and risk of endometriosis. \nHum Reprod (Oxf, Engl) 19(8):1755–1759. https:// doi. org/ 10. 1093/ hum-\nrep/ deh395\n 17. Gibbons RD, Clark DC, Fawcett J (1990) A statistical method for evaluating \nsuicide clusters and implementing cluster surveillance. Am J Epidemiol \n132(1 Suppl):S183–S191. https:// doi. org/ 10. 1093/ oxfor djour nals. aje. a1157 \n81\n 18. Rice VM (2002) Conventional medical therapies for endometriosis. Ann N \nY Acad Sci 955:343–552. https:// doi. org/ 10. 1111/j. 1749- 6632. 2002. tb027 \n95.x\n 19. Brown J, Crawford TJ, Allen C, Hopewell S, Prentice A (2017) Nonsteroi-\ndal anti-inflammatory drugs for pain in women with endometriosis. \nCochrane Database Syst Rev. https:// doi. org/ 10. 1002/ 14651 858. CD004 \n753. pub4\n 20. Nardo L, Chouliaras S (2020) Adjuvants in IVF—evidence for what works \nand what does not work. Upsala J Med Sci 125(2):144–151. https:// doi. \norg/ 10. 1080/ 03009 734. 2020. 17517 51\n 21. Vercellini P , Somigliana E, Viganò P , Abbiati A, Barbara G, Crosignani PG \n(2009) Endometriosis: current therapies and new pharmacological devel-\nopments. Drugs 69(6):649–675. https:// doi. org/ 10. 2165/ 00003 495- 20096 \n9060- 00002\n 22. Nothnick BW, Marsh C, Alali Z (2018) Future directions in endometrio-\nsis research and therapeutics. Curr Women Health Rev 14(2):189–194. \nhttps:// doi. org/ 10. 2174/ 15734 04813 66616 12211 64810\n 23. Selçuk I, Bozdağ G (2013) Recurrence of endometriosis; risk factors, \nmechanisms and biomarkers; review of the literature. J. Turkish Ger \nGynecol Assoc 14(2):98–103. https:// doi. org/ 10. 5152/ jtgga. 2013. 52385\n 24. Morotti M, Remorgida V, Venturini PL, Ferrero S (2014) Progestogen-only \ncontraceptive pill compared with combined oral contraceptive in the \ntreatment of pain symptoms caused by endometriosis in patients with \nmigraine without aura. Eur J Obstet Gynecol Reprod Biol 179:63–68. \nhttps:// doi. org/ 10. 1016/j. ejogrb. 2014. 05. 016\n 25. Giudice LC, As-Sanie S, Arjona Ferreira JC, Becker CM, Abrao MS, Lessey \nBA, Brown E, Dynowski K, Wilk K, Li Y, Mathur V, Warsi QA, Wagman RB, \nJohnson NP (2022) Once daily oral relugolix combination therapy versus \nplacebo in patients with endometriosis-associated pain: two replicate \nphase 3, randomised, double-blind, studies (SPIRIT 1 and 2). Lancet \n399(10343):2267–2279. https:// doi. org/ 10. 1016/ S0140- 6736(22) 00622-5\n 26. Ilhan M, Gürağaç Dereli TF, Akkol KE (2019) Novel drug targets with tradi-\ntional herbal medicines for overcoming endometriosis. Curr Drug Deliv \n16(5):386–399. https:// doi. org/ 10. 2174/ 15672 01816 66618 12271 12421\n 27. Xu H, Lui WT, Chu CY, Ng PS, Wang CC, Rogers MS (2008) Anti-angiogenic \neffects of green tea catechin on an experimental endometriosis mouse \nmodel. Hum Reprod 24(3):608–618. https:// doi. org/ 10. 1093/ humrep/ \nden417% JHuma nRepr oduct ion\n 28. Arablou T, Kolahdouz-Mohammadi R (2018) Curcumin and endome-\ntriosis: review on potential roles and molecular mechanisms. Biomed \nPharmacother 97:91–7. https:// doi. org/ 10. 1016/j. biopha. 2017. 10. 119\n 29. Wang D, Liu Y, Han J, Zai D, Ji M, Cheng W, Xu L, Yang L, He M, Ni J, Cai Z, \nYu C (2011) Puerarin suppresses invasion and vascularization of endome-\ntriosis tissue stimulated by 17β-Estradiol. PLOS ONE 6(9):e25011. https:// \ndoi. org/ 10. 1371/ journ al. pone. 00250 11\n 30. Boonchird C, Mahapanichkul T, Cherdshewasart W (2010) Differential \nbinding with ERalpha and ERbeta of the phytoestrogen-rich plant Puer-\naria mirifica. Braz J Med Biol Res 43(2):195–200. https:// doi. org/ 10. 1590/ \ns0100- 879x2 00900 75000 26\n 31. Hwang YP , Jeong HG (2008) Mechanism of phytoestrogen puerarin-\nmediated cytoprotection following oxidative injury: estrogen receptor-\ndependent up-regulation of PI3K/Akt and HO-1. Toxicol Appl Pharmacol \n233(3):371–381. https:// doi. org/ 10. 1016/j. taap. 2008. 09. 006\n 32. Yu J, Zhao L, Zhang D, Zhai D, Shen W, Bai L, Liu Y, Cai Z, Li J, Yu C (2015) \nThe effects and possible mechanisms of puerarin to treat endometriosis \nmodel rats. Evid Based Complement Alternat Med 2015:269138. https:// \ndoi. org/ 10. 1155/ 2015/ 269138\n 33. Barbara G, Buggio L, Facchin F, Vercellini P (2021) Medical Treatment for \nEndometriosis: Tolerability, Quality of Life and Adherence. Front Glob \nWomen Health 2:729601. https:// doi. org/ 10. 3389/ fgwh. 2021. 729601\n 34. Reis FM, Petraglia F, Taylor RN (2013) Endometriosis: hormone regulation \nand clinical consequences of chemotaxis and apoptosis. Hum Reprod \nUpdate 19(4):406–418. https:// doi. org/ 10. 1093/ humupd/ dmt010\n 35. Donnez J, Binda MM, Donnez O, Dolmans MM (2016) Oxidative stress in \nthe pelvic cavity and its role in the pathogenesis of endometriosis. Fertil \nSteril 106(5):1011–1017. https:// doi. org/ 10. 1016/j. fertn stert. 2016. 07. 1075\n 36. Vercellini P , Pietropaolo G, De Giorgi O, Pasin R, Chiodini A, Crosignani \nPG (2005) Treatment of symptomatic rectovaginal endometriosis with \nan estrogen-progestogen combination versus low-dose norethindrone \nacetate. Fertil Steril 84(5):1375–1387. https:// doi. org/ 10. 1016/j. fertn stert. \n2005. 03. 083\n\nPage 18 of 19Shah et al. Future Journal of Pharmaceutical Sciences           (2024) 10:35 \n 37. Vercellini P , Frontino G, De Giorgi O, Pietropaolo G, Pasin R, Crosignani \nPG (2003) Continuous use of an oral contraceptive for endometriosis-\nassociated recurrent dysmenorrhea that does not respond to a cyclic \npill regimen. Fertil Steril 80(3):560–563. https:// doi. org/ 10. 1016/ s0015- \n0282(03) 00794-5\n 38. Vercellini P , Barbara G, Somigliana E, Bianchi S, Abbiati A, Fedele L (2010) \nComparison of contraceptive ring and patch for the treatment of symp-\ntomatic endometriosis. Fertil Steril 93(7):2150–2161. https:// doi. org/ 10. \n1016/j. fertn stert. 2009. 01. 071\n 39. Vercellini P , Buggio L, Berlanda N, Barbara G, Somigliana E, Bosari S (2016) \nEstrogen-progestins and progestins for the management of endome-\ntriosis. Fertil Steril 106(7):1552–71.e2. https:// doi. org/ 10. 1016/j. fertn stert. \n2016. 10. 022\n 40. Kumar P , Sharma A (2014) Gonadotropin-releasing hormone analogs: \nUnderstanding advantages and limitations. J Hum Reprod Sci 7(3):170–\n174. https:// doi. org/ 10. 4103/ 0974- 1208. 142476\n 41. Küpker W, Felberbaum RE, Krapp M, Schill T, Malik E, Diedrich K (2002) Use \nof GnRH antagonists in the treatment of endometriosis. Reprod Biomed \nOnline 5(1):12–16. https:// doi. org/ 10. 1016/ S1472- 6483(10) 61590-8\n 42. Taylor HS, Giudice LC, Lessey BA, Abrao MS, Kotarski J, Archer DF, Dia-\nmond MP , Surrey E, Johnson NP , Watts NB, Gallagher JC, Simon JA, Carr BR, \nDmowski WP , Leyland N, Rowan JP , Duan WR, Ng J, Schwefel B, Thomas \nJW, Jain RI, Chwalisz K (2017) Treatment of endometriosis-associated \npain with Elagolix, an oral GnRH antagonist. N Engl J Med 377(1):28–40. \nhttps:// doi. org/ 10. 1056/ NEJMo a1700 089\n 43. Kim JJ, Kurita T, Bulun SE (2013) Progesterone action in endometrial \ncancer, endometriosis, uterine fibroids, and breast cancer. Endocr Rev \n34(1):130–162. https:// doi. org/ 10. 1210/ er. 2012- 1043% JEndo crine Revie ws\n 44. Abdul Karim AK, Shafiee MN, Abd Aziz NH, Omar MH, Abdul Ghani NA, \nLim PS, Md Zin RR, Mokhtar N (2019) Reviewing the role of progesterone \ntherapy in endometriosis. Gynecol Endocrinol 35(1):10–16. https:// doi. \norg/ 10. 1080/ 09513 590. 2018. 14904 04\n 45. Avraham S, Seidman DS (2014) Surgery versus pharmacological treat-\nment for endometriosis. Women’s Health 10(2):161–166. https:// doi. org/ \n10. 2217/ whe. 13. 77\n 46. Brichant G, Laraki I, Henry L, Munaut C, Nisolle M (2021) New therapeutics \nin endometriosis: a review of hormonal, non-hormonal, and non-coding \nRNA treatments. Int J Mol Sci 22(19):10498\n 47. Guo SW, Groothuis PG (2018) Is it time for a paradigm shift in drug \nresearch and development in endometriosis/adenomyosis? Hum Reprod \nUpdate 24(5):577–598. https:// doi. org/ 10. 1093/ humupd/ dmy020\n 48. Fu J, Song H, Zhou M, Zhu H, Wang Y, Chen H, Huang W (2017) Progester-\none receptor modulators for endometriosis. Cochrane Database Syst Rev. \nhttps:// doi. org/ 10. 1002/ 14651 858. CD009 881. pub2\n 49. García-Gómez E, Vázquez-Martínez ER, Reyes-Mayoral C, Cruz-Orozco \nOP , Camacho-Arroyo I, Cerbón M (2020) Regulation of inflammation \npathways and inflammasome by sex steroid hormones in endometriosis. \nFront Endocrinol 10:935. https:// doi. org/ 10. 3389/ fendo. 2019. 00935\n 50. Chen F-Y, Wang X, Tang R-Y, Guo Z-X, Deng Y-Z-J, Yu Q, Shi Q (2019) New \ntherapeutic approaches for endometriosis besides hormonal therapy. \nChin Med J 132(24):2984–93. https:// doi. org/ 10. 1097/ CM9. 00000 00000 \n000569\n 51. Moehner S, Becker K, Lange JA, von Stockum S, Serrani M, Heinemann K \n(2021) Long-term treatment of endometriosis with dienogest: real-world \nresults from the VIPOS study. J Endometr Pelvic Pain Disord 13(2):104–\n110. https:// doi. org/ 10. 1177/ 22840 26521 993688\n 52. Berlanda N, Somigliana E, Frattaruolo MP , Buggio L, Dridi D, Vercellini P \n(2017) Surgery versus hormonal therapy for deep endometriosis: is it \na choice of the physician? Eur J Obst Gynecol Reprod Biol 209:67–71. \nhttps:// doi. org/ 10. 1016/j. ejogrb. 2016. 07. 513\n 53. Cezar TC, Schweppe KW, Pletzer KR, Becker S, Krentel H, Torres-De La \nRoche LA, De Wilde RL (2018) The cost-effective, but forgotten, medical \nendometriosis therapy: a prospective, quasi-randomized study on pro-\ngestin therapy. Facts Views Vis ObGyn 10(4):181–190\n 54. Soliman AM, Surrey E, Bonafede M, Nelson JK, Castelli-Haley J (2018) \nReal-world evaluation of direct and indirect economic burden among \nendometriosis patients in the United States. Adv Ther 35(3):408–423. \nhttps:// doi. org/ 10. 1007/ s12325- 018- 0667-3\n 55. Simoens S, Dunselman G, Dirksen C, Hummelshoj L, Bokor A, Brandes I, \nBrodszky V, Canis M, Colombo GL, DeLeire T, Falcone T, Graham B, Halis \nG, Horne A, Kanj O, Kjer JJ, Kristensen J, Lebovic D, Mueller M, Vigano P , \nWullschleger M, D’Hooghe T (2012) The burden of endometriosis: costs \nand quality of life of women with endometriosis and treated in referral \ncentres. Hum Reprod 27(5):1292–1299. https:// doi. org/ 10. 1093/ humrep/ \ndes073% JHuma nRepr oduct ion\n 56. Guo S-W (2009) Recurrence of endometriosis and its control. Hum \nReprod Update 15(4):441–461. https:// doi. org/ 10. 1093/ humupd/ \ndmp007% JHuma nRepr oduct ionUp date\n 57. Barra F, Scala C, Mais V, Guerriero S, Ferrero S (2018) Investigational drugs \nfor the treatment of endometriosis, an update on recent developments. \nExpert Opin Investig Drugs 27(5):445–458. https:// doi. org/ 10. 1080/ 13543 \n784. 2018. 14711 35\n 58. Surrey ES, Silverberg KM, Surrey MW, Schoolcraft WB (2002) Effect of \nprolonged gonadotropin-releasing hormone agonist therapy on the out-\ncome of in vitro fertilization-embryo transfer in patients with endome-\ntriosis. Fertil Steril 78(4):699–704. https:// doi. org/ 10. 1016/ S0015- 0282(02) \n03373-3\n 59. DiVasta AD, Feldman HA, Sadler Gallagher J, Stokes NA, Laufer MR, Horn-\nstein MD, Gordon CM (2015) Hormonal add-back therapy for females \ntreated with gonadotropin-releasing hormone agonist for endometriosis: \na randomized controlled trial. Obstet Gynecol 126(3):617–627. https:// doi. \norg/ 10. 1097/ aog. 00000 00000 000964\n 60. DiVasta AD, Stamoulis C, Gallagher JS, Laufer MR, Anchan R, Hornstein MD \n(2021) Nonhormonal therapy for endometriosis: a randomized, placebo-\ncontrolled, pilot study of cabergoline versus norethindrone acetate. F&S \nRep 2(4):454–461. https:// doi. org/ 10. 1016/j. xfre. 2021. 07. 003\n 61. Kaponis A, Chatzopoulos G, Paschopoulos M, Georgiou I, Paraskevaidis V, \nZikopoulos K, Tsiveriotis K, Taniguchi F, Adonakis G, Harada T (2020) Ultra-\nlong administration of gonadotropin-releasing hormone agonists before \nin vitro fertilization improves fertilization rate but not clinical pregnancy \nrate in women with mild endometriosis: a prospective, randomized, \ncontrolled trial. Fertil Steril 113(4):828–835. https:// doi. org/ 10. 1016/j. fertn \nstert. 2019. 12. 018\n 62. Harada T, Momoeda M, Taketani Y, Aso T, Fukunaga M, Hagino H, Terakawa \nN (2009) Dienogest is as effective as intranasal buserelin acetate for the \nrelief of pain symptoms associated with endometriosis—a randomized, \ndouble-blind, multicenter, controlled trial. Fertil Steril 91(3):675–681. \nhttps:// doi. org/ 10. 1016/j. fertn stert. 2007. 12. 080\n 63. Donnez J, Dolmans M-M (2021) Endometriosis and medical therapy: from \nprogestogens to progesterone resistance to GnRH antagonists: a review. \nJ Clin Med 10(5):1085\n 64. Laschke MW, Schwender C, Scheuer C, Vollmar B, Menger MD (2008) \nEpigallocatechin-3-gallate inhibits estrogen-induced activation of \nendometrial cells in vitro and causes regression of endometriotic lesions \nin vivo. Hum Reprod 23(10):2308–2318. https:// doi. org/ 10. 1093/ humrep/ \nden245% JHuma nRepr oduct ion\n 65. Ricci AG, Olivares CN, Bilotas MA, Bastón JI, Singla JJ, Meresman GF, \nBarañao RI (2013) Natural therapies assessment for the treatment of \nendometriosis. Hum Reprod (Oxf Engl) 28(1):178–188. https:// doi. org/ 10. \n1093/ humrep/ des369\n 66. Sharifi-Rad J, Rayess YE, Rizk AA, Sadaka C, Zgheib R, Zam W, Sestito S, \nRapposelli S, Neffe-Skocińska K, Zielińska D, Salehi B, Setzer WN, Dosoky \nNS, Taheri Y, El Beyrouthy M, Martorell M, Ostrander EA, Suleria HAR, Cho \nWC, Maroyi A, Martins N (2020) Turmeric and its major compound cur-\ncumin on health: bioactive effects and safety profiles for food, pharma-\nceutical, biotechnological and medicinal applications. Front Pharmacol \n11:1021. https:// doi. org/ 10. 3389/ fphar. 2020. 01021\n 67. Cao Y, Ye Q, Zhuang M, Xie S, Zhong R, Cui J, Zhou J, Zhu Y, Zhang T, Cao L \n(2017) Ginsenoside Rg3 inhibits angiogenesis in a rat model of endome-\ntriosis through the VEGFR-2-mediated PI3K/Akt/mTOR signaling pathway. \nPLOS ONE 12(11):e0186520. https:// doi. org/ 10. 1371/ journ al. pone. 01865 \n20\n 68. Huang R, Chen S, Zhao M, Li Z, Zhu L (2020) Ginsenoside Rg3 attenuates \nendometriosis by inhibiting the viability of human ectopic endometrial \nstromal cells through the nuclear factor-kappaB signaling pathway. J \nGynecol Obstet Hum Reprod 49(1):101642. https:// doi. org/ 10. 1016/j. \njogoh. 2019. 101642\n 69. Dull A-M, Moga MA, Dimienescu OG, Sechel G, Burtea V, Anastasiu CV \n(2019) Therapeutic approaches of resveratrol on endometriosis via anti-\ninflammatory and anti-angiogenic pathways. Molecules 24(4):667\n 70. Athar M, Back JH, Kopelovich L, Bickers DR, Kim AL (2009) Multiple \nmolecular targets of resveratrol: anti-carcinogenic mechanisms. Arch \n\nPage 19 of 19\nShah et al. Future Journal of Pharmaceutical Sciences           (2024) 10:35 \n \nBiochem Biophys 486(2):95–102. https:// doi. org/ 10. 1016/j. abb. 2009. 01. \n018\n 71. Brito PM, Devillard R, Nègre-Salvayre A, Almeida LM, Dinis TC, Salvayre R, \nAugé N (2009) Resveratrol inhibits the mTOR mitogenic signaling evoked \nby oxidized LDL in smooth muscle cells. Atherosclerosis 205(1):126–134. \nhttps:// doi. org/ 10. 1016/j. ather oscle rosis. 2008. 11. 011\n 72. Chan AY, Dolinsky VW, Soltys CL, Viollet B, Baksh S, Light PE, Dyck JR (2008) \nResveratrol inhibits cardiac hypertrophy via AMP-activated protein kinase \nand Akt. J Biol Chem 283(35):24194–24201. https:// doi. org/ 10. 1074/ jbc. \nM8028 69200\n 73. Manach C, Scalbert A, Morand C, Rémésy C, Jiménez L (2004) Polyphe-\nnols: food sources and bioavailability. Am J Clin Nutr 79(5):727–747. \nhttps:// doi. org/ 10. 1093/ ajcn/ 79.5. 727\n 74. Balan A, Moga MA, Dima L, Dinu CG, Martinescu CC, Panait DE, Irimie \nCA, Anastasiu CV (2021) An overview on the conservative management \nof endometriosis from a naturopathic perspective: phytochemicals and \nmedicinal plants. Plants 10(3):587\n 75. Taniguchi F, Tagashira Y, Suou K, Iwabe T, Harada T (2009) Apigenin inhib-\nits TNFα-induced cell proliferation in endometriotic stromal cells. Fertil \nSteril 92(3):S11. https:// doi. org/ 10. 1016/j. fertn stert. 2009. 07. 042\n 76. Dean M, Austin J, Jinhong R, Johnson ME, Lantvit DD, Burdette JE (2018) \nThe flavonoid apigenin is a progesterone receptor modulator with in vivo \nactivity in the uterus. Horm Cancer 9(4):265–277. https:// doi. org/ 10. 1007/ \ns12672- 018- 0333-x\n 77. Park S, Lim W, Bazer FW, Song G (2017) Apigenin induces ROS-dependent \napoptosis and ER stress in human endometriosis cells. J Cell Physiol \n233(4):3055–3065. https:// doi. org/ 10. 1002/ jcp. 26054\n 78. Abbas MA, Taha MO, Zihlif MA, Disi AM (2013) β-Caryophyllene causes \nregression of endometrial implants in a rat model of endometriosis \nwithout affecting fertility. Eur J Pharmacol 702(1):12–19. https:// doi. org/ \n10. 1016/j. ejphar. 2013. 01. 011\n 79. Francomano F, Caruso A, Barbarossa A, Fazio A, La Torre C, Cera-\nmella J, Mallamaci R, Saturnino C, Iacopetta D, Sinicropi MS (2019) \nβ-Caryophyllene: a sesquiterpene with countless biological properties. \nAppl Sci 9(24):5420\n 80. Kim C, Cho SK, Kim K-D, Nam D, Chung W-S, Jang H-J, Lee S-G, Shim BS, \nSethi G, Ahn KS (2014) β-Caryophyllene oxide potentiates TNFα-induced \napoptosis and inhibits invasion through down-modulation of NF-κB-\nregulated gene products. Apoptosis 19(4):708–718. https:// doi. org/ 10. \n1007/ s10495- 013- 0957-9\n 81. Bina F, Soleymani S, Toliat T, Hajimahmoodi M, Tabarrai M, Abdollahi M, \nRahimi R (2019) Plant-derived medicines for treatment of endometrio-\nsis: a comprehensive review of molecular mechanisms. Pharmacol Res \n139:76–90. https:// doi. org/ 10. 1016/j. phrs. 2018. 11. 008\n 82. Bitto A, Granese R, Polito F, Triolo O, Giordano D, Squadrito F, Danna R, \nSantamaria A (2015) Genistein reduces angiogenesis and apoptosis in \nwomen with endometrial hyperplasia. Bot Targets Ther. https:// doi. org/ \n10. 2147/ btat. s67368\n 83. Liu M, Hansen PE, Wang G, Qiu L, Dong J, Yin H, Qian Z, Yang M, Miao J \n(2015) Pharmacological profile of xanthohumol, a prenylated flavonoid \nfrom hops (Humulus lupulus). Molecules 20(1):754–779\n 84. Kong S, Zhang Y-H, Liu C-F, Tsui I, Guo Y, Ai B-B, Han F-J (2014) The \ncomplementary and alternative medicine for endometriosis: a review \nof utilization and mechanism. Evid Based Complement Altern Med \n2014:146383. https:// doi. org/ 10. 1155/ 2014/ 146383\n 85. Guo Y, Liu F-Y, Shen Y, Xu J-Y, Xie L-Z, Li S-Y, Ding D-N, Zhang D-Q, Han \nF-J (2021) Complementary and alternative medicine for dysmenorrhea \ncaused by endometriosis: a review of utilization and mechanism. Evid \nBased Complement Alternat Med 2021:6663602. https:// doi. org/ 10. 1155/ \n2021/ 66636 02\n 86. Wu X, Ng EHY, Stener-Victorin E, Legro RS (2014) Effects and mechanisms \nof complementary and alternative medicine during the reproductive \nprocess. Evid Based Complement Alternat Med 2014:698921. https:// doi. \norg/ 10. 1155/ 2014/ 698921\n 87. Ding Z, Lian F (2015) Traditional Chinese medical herbs staged therapy \nin infertile women with endometriosis: a clinical study. Int J Clin Exp Med \n8(8):14085–14089\n 88. Zhao RH, Hao ZP , Zhang Y, Lian FM, Sun WW, Liu Y, Wang R, Long L, Cheng \nL, Ding YF, Song DR, Meng QW, Wang AM (2013) Controlling the recur-\nrence of pelvic endometriosis after a conservative operation: comparison \nbetween Chinese herbal medicine and western medicine. Chin J Integr \nMed 19(11):820–825. https:// doi. org/ 10. 1007/ s11655- 012- 1247-z\n 89. Xu H, Lui WT, Chu CY, Ng PS, Wang CC, Rogers MS (2009) Anti-angiogenic \neffects of green tea catechin on an experimental endometriosis mouse \nmodel. Hum Reprod (Oxf, Engl) 24(3):608–618. https:// doi. org/ 10. 1093/ \nhumrep/ den417\n 90. Abbas MA, Taha MO, Zihlif MA, Disi AM (2013) β-Caryophyllene causes \nregression of endometrial implants in a rat model of endometriosis with-\nout affecting fertility. Eur J Pharmacol 702(1–3):12–19. https:// doi. org/ 10. \n1016/j. ejphar. 2013. 01. 011\n 91. Kamal DAM, Salamt N, Zaid SSM, Mokhtar MH (2021) Beneficial effects \nof green tea catechins on female reproductive disorders: a review. Mol-\necules 26(9):2675\n 92. Amirsalari S, Behboodi Moghadam Z, Taghizadeh Z, Jafar Abadi MN, \nSabaghzadeh Irani P , Goodarzi S, Ranjbar H (2021) The effect of garlic \ntablets on the endometriosis-related pains: a randomized placebo-con-\ntrolled clinical trial. Evid Based Complement Alternat Med 2021:5547058. \nhttps:// doi. org/ 10. 1155/ 2021/ 55470 58\n 93. Dysmenorrhea and Endometriosis in the Adolescent\n 94. Kiani K, Sadati Lamardi SN, Laschke MW, Malekafzali Ardakani H, Mova-\nhedin M, Ostad SN, Aflatoonian R, Moini A (2016) Medicinal plants and \nnatural compounds in the treatment of experimental endometriosis: a \nsystematic review protocol. Evid Based Preclin Med 3(2):e00019. https:// \ndoi. org/ 10. 1002/ ebm2. 19\n 95. Park KS (2019) The efficacy and safety of Korean herbal medicine in \na patient with endometrioma of the ovary: a case report. Explore \n15(2):142–147. https:// doi. org/ 10. 1016/j. explo re. 2018. 06. 007\n 96. Sinclair J, Abbott J, Mikocka-Walus A, Ng C, Sarris J, Evans S, Armour M \n(2023) ‘A glimmer of hope’: perceptions, barriers, and drivers for medicinal \ncannabis use amongst Australian and New Zealand people with endo-\nmetriosis: a qualitative study. Reprod Fertility 4(4):e230049. https:// doi. \norg/ 10. 1530/ RAF- 23- 0049\n 97. Sinclair J, Abbott J, Proudfoot A, Armour M (2023) The place of cannabi-\nnoids in the treatment of gynecological pain. Drugs 83(17):1571–1579. \nhttps:// doi. org/ 10. 1007/ s40265- 023- 01951-z\n 98. Zamawe C, King C, Jennings HM, Mandiwa C, Fottrell E (2018) Effective-\nness and safety of herbal medicines for induction of labour: a systematic \nreview and meta-analysis. BMJ Open 8(10):e022499. https:// doi. org/ 10. \n1136/ bmjop en- 2018- 022499\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in pub-\nlished maps and institutional affiliations.","source_license":"CC0","license_restricted":false}