A comprehensive review comparing conventional versus traditional remedies in the treatment of endometriosis with futuristic insights

Background A common condition known as endometriosis typically takes place in females in their reproductive age and develops generally in the endometrial lining of females. Chronically, endometriosis has been associated with a reduction in the patient’s quality of life (QOL) which can have a hazardous impact on their social working and functionality. Owing to the involvement of hormones in the development of endometriosis, drugs having the capability to modulate the hormonal concentrations, along with surgical techniques, have been designed to treat endometriosis. Main body There are certain drawbacks of the currently existing therapy for endometriosis which include the inabil- ity to improve the quality of life of the patient, treatment failures and unresponsiveness from the patient, and adverse effects of the drugs such as weight gain, mood swings, vaginal dryness, etc. Herbal medicines have attracted the attention of various researchers for the development of novel therapeutics against several gynecological disor- ders, mainly endometriosis. Our present review summarizes the precise pathogenesis of endometriosis along with its conventional therapy and novel developments in herbal medicines wherein we have compiled data from 15 com- pleted clinical trials (conventional therapy: 7, herbal therapy: 8). Additionally, we have included data from four pre- clinical studies on herbal medicine that showed promising results in treating endometriosis highlighting the neces- sity for clinical trials to yield more definitive findings. The number of clinical trials carried out to assess the response of herbs in endometriosis is limited which is why additional studies could provide beneficial concrete evidence in the effective treatment of endometriosis and ensure improved patient outcomes.

Conventional therapies possess certain limitations to treat endometriosis due to which the attention of scientists has shifted toward herbal therapy due to its advantages such as improved safety and tolerability in treat- ing endometriosis. However, additional clinical investigations into herbal therapy may prove to be fruitful in the dis- covery of novel therapeutics to treat endometriosis effectively.

Estrogen, Progesterone, Conventional therapy, Herbal therapy, Endometriosis, GnRH agonist Open Access © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Future Journal of Pharmaceutical Sciences *Correspondence: Nisha Parikh [email protected] Full list of author information is available at the end of the article Page 2 of 19Shah et al. Future Journal of Pharmaceutical Sciences (2024) 10:35

The endometrium constitutes the deepest layer of the uterus located within the female reproductive system, and it is composed of luminal and glandular epithelial cells [1, 2]. Any damage to the endothelial layer may dis - rupt the process of implantation and may lead to endo - metriosis (Fig. 1) [3–5]. Endometriosis can be identified by the development of tissues similar to endometrial tissues that grow out - side of the uterine lining that can cause pain in the pelvic region and on a chronic basis may also lead to infertility. It usually occurs in females that are in their reproduc - tive age, i.e., 18–54 years [6]. Although the exact factors or mechanisms behind endometriosis are still unknown, several theories have been proposed as to how its lesions arise [7]. Several symptoms arise due to endometriosis including intermenstrual bleeding, irregularity in menses (dysmenorrhea), dyschezia, dysuria, and also disruption in quality of life among patients which makes it a critical disease that needs to be dealt with [7, 8]. According to estimates, endometriosis usually is noticed in females falling between 18 and 54 years of age Fig. 1 An illustrative diagram representing the various factors causing endometriosis and the role of inflammation in its pathogenesis. Due to several factors including genetic, environmental, and lifestyle factors, dysfunction of the hypothalamic-pituitary axis (HPA-axis) takes place following which the production of female reproductive hormones such as LH, FSH, Anti-mullein hormone (AMH), etc. becomes impaired leading to an imbalance ultimately resulting in the release of inflammatory markers due to initiation process of inflammation. This can lead to damage in the endometrial layer and result in the formation of endometrial lesions resulting in pelvic pain and enlargement of the endometrium causing Endometriosis Page 3 of 19 Shah et al. Future Journal of Pharmaceutical Sciences (2024) 10:35 with its proportion of incidences varying from 10 to 15% [9]. The development of this disease has been observed to take place in up to 50% of women that have experienced infertility along with 47% of adults that have undergone laparoscopic procedures at some point in their life expe - riencing pelvic discomfort [7]. When the race-wise risk was calculated to develop endometriosis, it was noted that the Asian women population was at the highest risk of developing endometriosis, while black women were observed to possess the highest possibility to develop endometriosis [10]. It has been observed that the preva - lence of endometriosis in developed countries such as the USA, Russia, China, etc., was found to be 20% [11]. Similarly, the incidence rate of endometriosis was found to range from 34 to 48% in developing countries such as India [12]. Hormonal imbalances and their alterations can lead to elevations in the probability to develop endo - metriosis. Along with these menstrual factors, the early age at which menstruation commences and reduced menstrual period  may also influence the likelihood of endometriosis [13–15]. Furthermore, lifestyle factors such as caffeine and alcohol intake are also associated with the development of endometriosis [16, 17]. Several factors leading to endometriosis are highlighted in Fig. 2. The conventional therapies for the management of endometriosis include hormonal agents (norethin - drone, medroxyprogesterone acetate, cyproterone acetate, dienogest), contraceptive pills (estrogen–pro - gesterone, progestin), gonadotrophin-releasing hormone (GnRH) agonists (leuprolide, buserelin) and antagonists (cetrorelix, ganirelix), and  selective estrogen receptor modulator (tamoxifen, raloxifene) [18]. Patients suffering from endometriosis are known to experience pain in their pelvic region along with abdominal pain due to which they are usually given non-steroidal anti-inflammatory drugs (NSAIDs) to relieve them from their complaints of pain and steroids to regulate inflammation occurring in the endometrial region [19–21]. The majority of therapies designed to combat endome - triosis are dependent on estrogen and other hormones as they constitute a majority of the disease’s etiopathogen - esis [22]. However, there are certain limitations of con - ventional therapy used in endometriosis such as risk of recurrences, safety and efficacy issues, risk of develop - ment of adverse events, etc. [23–25]. Due to the toxic effects of synthetic drugs, more atten - tion has been shifted toward medicinal herbal drugs to cope with the harmful side effects of conventional ther - apy in various gynecological disorders. Herbal drugs have emerged as a more reliable source for the discov - ery of novel therapeutic approaches for endometriosis [26]. They target several mechanisms associated with endometriosis such as inflammatory markers, estrogen receptors, growth factors responsible for the angiogen - esis of endometrial tissues, etc. The herb Epigallocatechin Gallate (EGCG) was shown to reduce inflammation by suppressing the release of NF-κB  along with mitogen- activated protein kinase 1 (MAPK-1) in the endometrial lesions  [27]. Similarly, Curcumin and Ginsenoside Rg3 can inhibit the effects of vascular endothelial-derived Fig. 2 Factors leading to endometriosis. Several factors may lead to endometriosis that include Genetic susceptibility towards particular genes, Immunological factors such as the stimulation of certain immune cells comprising Natural Killer cells, etc., Environmental factors such as exposure to some trigger chemicals and lastly the activation of inflammatory markers such as Interleukins (IL-1,3), NF-κβ, and TNF-α Page 4 of 19Shah et al. Future Journal of Pharmaceutical Sciences (2024) 10:35 growth factor (VEGF) necessary for angiogenesis of the endometrial lining in rats suggesting their potency in endometriosis [28]. Furthermore, Curcumin, Ginseno - side Rg3, Resveratrol, Apegenin, and β-Caryophyllene decrease the levels of IL-6, IL-8, and NF-κB in human endometrial stromal cells. Also, Puerarin, Resveratrol, Curcumin, Ginsenoside Rg3, Genistein, and Herbal decoction method have been shown to attach to estro - genic receptors and compete with 17β-estradiol (E2), thereby inhibiting the production of estrogen. Their probable mechanism in endometriosis is to suppress the vascularization of the endometrial cells by targeting estrogen as it blocks the synthesis of estrogen through repression of the expression of aromatase cytochrome P450 (p450arom)  in the endothelial stromal tissues as shown in Fig. 3 [29–32]. The present review compares conventional and herbal therapy based on literature evidences with the objective to identify prospective novel targets in the treatment of endometriosis. A literature search was conducted through an electronic database (PubMed, Medline, Clinicaltrials.gov, etc.) up to September 2023. The Fig. 3 An illustration representing the various sites at which herbs act in lowering the progression of endometriosis. Several traditional herbs possess many properties through which they can influence the progression of endometriosis such as Anti-oxidative (Ginsenoside, Apigenin, β-Caryophyllene), Anti-inflammatory (EGCG, Ginsenoside Rg3, Xanthohumol, Geinstein), Hormone regulatory effects (Puerin, Resveratrol, Genistein), and Anti-apoptotic effects (Ginsenoside). These herbs can work individually or in combination to treat the underlying causes of Endometriosis Page 5 of 19 Shah et al. Future Journal of Pharmaceutical Sciences (2024) 10:35 following key words were entered for search strategy: Endometriosis, Conventional therapy, GnRH agonist, Estrogens, Progestins, Selective estrogen receptor modu - lators (SERMs), Non-steroidal anti-inflammatory drugs (NSAIDs), Herbal therapy, Traditional medicine, Gen - istein, Curcumin, Ginsenoside Rg3, Herbal decoction method, Puerarin, Resveratrol, etc. Literature sources were assessed based on this search strategy and included into the present review. Additionally, it gives insights into the various conventional therapy used for endometriosis along with their limitations and whether herbal medicine have any benefits over conventional therapies. Main Text Conventional therapy for endometriosis Estrogen–progestins and progestins Also termed combined hormonal contraceptives (CHCs), they are given to the patients in the form of combined pills containing both estrogen and progesterone to bal - ance the levels of female reproductive hormones. These pills are being administered to patients with endome - triosis for a long time [33]. Both hormones possess their individual properties in lowering the damaging effects of endometriosis on the female body. Estradiol has the unique characteristics of anti-apoptosis and anti-inflam - matory properties which can lower the amount of  the inflammation process occurring at the endometrium, while progesterone also possesses anti-inflammatory properties but promotes apoptosis. Estradiol has the unique characteristics of anti-apoptosis and anti-inflam - matory properties which can lower the amount of  the inflammation process occurring at the endometrium while progesterone also possesses anti-inflammatory properties but promotes apoptosis [34]. Moreover, they lessen or stop menstruation entirely, which limits the number of endometrial cells that reflux into the tubules. These pills contain a higher level of progestin while hav - ing a low level of estrogen. They are involved with regu - larizing the menstrual cycle. As a result of this, it would lead to a delay in the inflammation process and oxida - tive stress occurring within the endometrial layer [35]. There have been several investigations that have been conducted in this context, and it has been reported that about two-thirds of the female population have benefit - ted from estrogen–progestin therapy and their dysmen - orrhea also got corrected [33, 36–38]. Certain examples of progesterone include medroxyprogesterone, norethis - terone acetate, desogestrel, etc. [39]. Gonadotrophin‑releasing hormone (GnRH) agonists and antagonists The mechanism behind GnRH analogues is that they cause the pituitary gonadotrophs to be stimulated and further promote the release of follicle-stimulat - ing hormone (FSH), luteinizing hormone (LH), etc., thereby maintaining the normal female reproductive system  function and the endometrial lining [40]. An effective strategy to combat endometriosis includes the withdrawal of the hormone (estrogen) which can be provided by administering GnRH agonist. However, a higher estrogen withdrawal may result in unpredicted adverse events including bone density loss, altered men - tal status, and risk for cardiovascular disorders which can lead to osteoporosis [33, 41]. Elagolix is a common drug included within the category of GnRH agonists and is used for endometriosis and it has shown signifi - cant results under clinical investigations [42]. The utiliza- tion of GnRH antagonists in a similar manner to GnRH agonists has also been evaluated in endometriosis. On evaluation, it was observed that treatment with GnRH antagonists like Cetrorelix, Abarelix, and Ozarelix can ensure the successful inhibition of gonadotrophins while also maintaining the levels of estrogen in the body. Due to this, the adverse events noted with GnRH agonists can be reduced along with the progression of the disease [41]. Hence, endometriosis now has a new avenue for medical treatment due to the administration of Cetrorelix which is an GnRH antagonist. Progestins Another promising avenue for the treatment of endo - metriosis includes therapy with progesterone-only pills which are available in the market in several dosage forms such as transdermal patches, oral pills, intrauterine devices, etc. They have been associated with alleviation in pain and irregularity in menses along with limiting the size of the endometrial lesion [43]. They may act through various mechanisms such as inhibiting angiogenesis around the endometrial lining, inhibiting aromatase enzyme, catalyzing anovulation, modulating estrogen receptors, and decreasing the expression of 17β-HSD1 (hydroxysteroid dehydrogenase) [44]. Examples of pro - gestins include medroxyprogesterone acetate, norethin - drone, cyproterone acetate, lynesterole, etc. [45, 46] Selective estrogen receptor modulators (SERMs) and selective progesterone receptor modulators (SPRMs) These agents can attach themselves to estrogen or pro - gesterone receptors and modulate their function result - ing in modulating their signaling pathway. Due to this, the menstrual cycle gets restored due to regained bal - ance between the estrogen and progesterone hormone levels. Certain examples of SERMs include tamoxifen, raloxifene, bazedoxifene, etc., while of SPRMs include mifepristone, asoprisnil, lonaprisan, etc. [43, 47, 48]. However, there is no hormonal therapy for endometriosis Page 6 of 19Shah et al. Future Journal of Pharmaceutical Sciences (2024) 10:35 that is free from adverse events and a therapy should be designed in such a way that it doesn’t influence the nor - mal menstrual cycle of the body in any way and sub - sequently leads to endometrial lesion size reduction thereby decreasing the inflammation process occurring within it. Non‑steroidal anti‑inflammatory drugs As discussed above, inflammation is an important con - stituent in the development of endometriosis due to the release of prostaglandins and this ultimately leads to pain in the patient [49]. Due to this complaint of pain expe - rienced by the patients, NSAIDs can be prescribed as a supplemental therapy to relieve the patients from their pain symptoms [46]. Drugs such as mefenamic acid, nap - roxen sodium, ketoprofen, and ibuprofen at doses of 400 to 600 mg in the form of oral tablets for the duration of 6 to 9 months [19, 50]. Figure  4 shows a brief timeline for the development of various drugs used as conventional therapies to treat endometriosis along with their mechanisms of action. Shortcomings of conventional therapy in Endometriosis Conventional therapy for endometriosis has been shown to possess certain drawbacks which include: Tolerability issues There have been instances wherein the current treat - ment options for endometriosis (majorly hormonal agents) have not been successfully tolerated. Estrogen and progestins can be given in the form of combined oral contraceptives (COCs) to balance the hormonal levels of the body. However, they are associated with several adverse events due to which their tolerability decreases in patients [24]. Certain examples of adverse events of estrogens include vaginal bleeding and itching, irregular menstruation, menstrual bleeding, gastric disturbances, hot flushes, mood swings, etc. [33]. Almost all therapeu - tics of endometriosis have safety and tolerability issues which is why they need to be checked in patients before giving it on a chronic basis [33]. Similar to estrogen, pro - gestins are also associated with adverse events such as hirsutism, acne, mood alterations, and weight gain [43]. Safety and efficacy issues In some studies, it has been found that when monother - apy is given to patients suffering from endometriosis, there has not been the achievement of successful thera - peutic outcomes. In an clinical investigation performed by Giudice et  al., they observed that monotherapy with Relugolix is not to be given for chronic use [25]. Addi - tionally, Barbara and colleagues evaluated the safety and efficacy of GnRH agonists in endometriosis and observed that on a long-term basis, GnRH monotherapy can - not be administered to endometriosis patients it was not found to be safe for them due to the development of severe adverse events such as weight gain, hot flushes mood swings which were frequently noticed in patients [33]. In terms of oral progestins, conventional therapy has been linked to the development of various major adverse events such as neoplasms, malignancy, endocrine abnormalities, mental and behavioral disorders, and Fig. 4 A diagram representing the timeline for the development of therapeutics employed in endometriosis treatment. This figure shows a timely development of the conventional agents for endometriosis in a progressive manner. The conventional agents comprise Anti-androgens (Danazol), Progestins (Norethindrone acetate, Medroxyprogesterone acetate), GnRH antagonists (Elagolix), GnRH agonists (Gosrelin, Leuprolide, Nafrelin). The year of authorization along with their mechanisms in endometriosis has been provided in the above figure Page 7 of 19 Shah et al. Future Journal of Pharmaceutical Sciences (2024) 10:35 many more. The SAE incidence rate per 10,000 women- years was 3.67% in long-term oral progestin users (treat - ment for more than 15 months) and 4.16% in short-term users (therapy for less than 15  months) which is why patients receiving conventional therapies are more prone to develop adverse drug reactions (ADRs) [51]. Due to the limited efficacy and safety of the conventional treat - ments, the patient ultimately has to undergo surgical pro- cedures such as laparoscopy, hysterectomy, etc. [45, 52]. Cost issues Treating endometriosis poses a substantial economic burden on the patients with the costs of therapy. This is the reason why an emphasis must be made on the cost of the therapy given in endometriosis [53]. In a study carried out by Soliman et al. wherein they evaluated the total direct costs and incremental costs between endo - metriosis patient and non-endometriosis control groups, they found a significant difference in both and concluded that there is a significant incremental cost to be paid in endometriosis treatment as high as $10,002 and $2132 for direct and indirect incremental costs [54]. Also, the adverse events incurred during the course of endometri - osis and due to its treatment, such as pelvic pain, infer - tility, irregular menses, and mood swings add up to the incremental cost that the patient has to pay to deal with these complications [55]. Risk of recurrences The greatest risk that the currently available treatments pose is the risk of recurrence of the disease due to the limited efficacy of the drugs. In most cases, the rea - son behind this recurrence is the presence of residual lesions or from de novo cells [23]. It was observed that the recurrence rates of endometriosis were 40–50% at a 5-year interval and 21–23% at the end of 2 years. In addi - tion to this, the precise risk factors leading to the recur - rence of endometriosis have not been identified yet [56]. Recurrence of endometriosis has also been observed in post-operative patients who have undergone surgical procedures for endometriosis [56]. Thus, it is necessary to control the recurrences of endometriosis to ensure better therapeutic outcomes in patients. Clinical trial data of conventional therapy in endometriosis Completed clinical trials A list of completed clinical studies and trials for endome- triosis patients and their findings are provided in Table 1. Certain examples of landmark clinical trials assessing the potency of conventional therapy in endometriosis are given below. In a Phase-I randomized, multicentric trial performed to assess the efficacy and safety of Aromatase inhibitors (Anastrozole) and Progestin against Placebo in patients suffering from Endometriosis, 309 participants were recruited (NCT02203331). They were divided into four cohorts, (a) participants receiving Progestin (Levonorg - estrel), (b) participants receiving Anastrozole in com - bination with levonorgestrel, (c) participants receiving leuprolide, and (d) participants receiving Placebo for the duration of 12 weeks. It was observed that all the drugs led to an improvement in the mean duration of endo - metriosis-associated pelvic pain (EAPP) which led to a reduction in the days that patient presented with pelvic pain [57]. In a similar Phase III study involving 815 participants, the potency of Elagolix was determined in patients suf - fering from Moderate to Severe endometriosis induced pain. The participants were divided into three cohorts: (a) patients receiving Elagolix 150  mg QD for a dura - tion of 6 months, (b) patients receiving Elagolix 200 mg 4 times in a day for 6 months, and (c) patients receiving Placebo drug for a 6-month duration. It was observed after the treatment duration that Elagolix both lower and higher dose resulted in improvements in endometriosis- associated pelvic pain; however, adverse events such as hot flushes, increased serum lipid levels, increase in bone mineral density (BMD) was observed. Therefore, it was concluded that conventional therapy, although effective led to the development of adverse events in patients of endometriosis [42]. Suspended or terminated clinical trials There have been certain instances wherein patients suf - fering from endometriosis were administered conven - tional therapy led to the termination or suspension of the clinical trial due to certain complications occurring due to the conventional agents. An example of such trial includes a study in which 50 participants were enrolled who were clinically diagnosed with endome - triosis and were divided into two groups: (a) receiving Dienogest 2  mg per day and (b) receiving Levonorg - estrel (0.10  mg per day) in combination with ethinyl estradiol (0.02  mg per day) [62] are progestins which reduce endometrial lining thickness thus decreasing the chance of bleeding in patients of endometriosis [63]. The outcomes measured included the change in size of the endometrial lesions from their baseline observed via ultrasound within a time duration of 1 year. It was observed that Busrelin acetate which is a GnRH agonist was equally effective in treating endometriosis as Dien - ogest which is why these 2 drugs were given optionally to the patients. A significant improvement in the symp - toms experienced by the patients and their pain score was observed with patients that were administered Die - nogest. It also led to lower reduction in bone mineral Page 8 of 19Shah et al. Future Journal of Pharmaceutical Sciences (2024) 10:35 Table 1 A table showing the various completed clinical trials for conventional therapy in endometriosis Phase Study design No of participants Eligibility criteria Arms of the study Study findings Inference Study Phase IV A randomized, par- allel, open-label study to determine whether endometrial implantation markers predict embryo transfer fertilization outcomes in vitro in subjects already administered leuprolide acetate 37 participants Infertility patients, diag- nosis of endometriosis patients, patients who have regular menses, normal ovarian reserve testing Intervention: Leuprolide acetate in depot suspen- sion 3.75 mg intramuscu- lar every 28 days The study found that there were no sig- nificant differences for outcomes such as rate of fertilization, stimulation of gonado- trophin hormones, etc. A high rate of fertiliza- tion rates was observed in the group of patients who were administered GnRH regimen which led to a larger fre- quency of implantations within them It was concluded from this study that GnRH agonist administration in endo- metriosis can lead to an increase in the rates of pregnancies in com- parison to the conven- tional ovarian stimulation techniques Surrey et al. [58] Phase II A randomized parallel- assignment study to observe the effi- cacy of hormonal therapy in combination with GnRH agonist in patients suffering from endometriosis 53 participants Women aged 13–22 years, body weight between 18 and 30 kg/ m2, surgical diagnosis of endometriosis, willing to comply with study requirements Intervention: Norethin- drone acetate 5 mg orally + Conjugated equine estrogens 0.625 mg orally Control: Norethindrone acetate 5 mg + placebo capsule 1 pill daily At 12 months, the intervention group increased the bone mineral density (BMD) and the overall mineral content of the body, while the control group did not show these outcomes. Quality-of-life assessments showed greater improvements in physical functioning with the interventional group. There were no sig- nificant adverse events were reported Add-back therapy with norethindrone acetate led to preser- vation of the skeletal health in endometriosis patients, the combina- tion of norethindrone acetate and conjugated equine estrogens being led to higher elevations in the BMD of the body. The therapy was safe and effective, with no tol- erability issues DiVasta et al. [59] Phase II A randomized, parallel- assignment pilot study to determine the effect of dopamine receptor agonist therapy for pain relief in women suffering from endometriosis 10 participants Women with confirmed case of endome- triosis, age between 15 and 40 years Intervention 1: Cabergoline (0.5 mg PO two times a week for 6 months duration) Intervention 2: Norethin- drone acetate (5 mg po daily for 6 months) It was observed from this study that many subjects taking caber- goline experienced a decrease in pain scores and improvement in pain complaints compared to subjects treated with Norethindrone acetate. Cabergoline was also well tolerated by the patients It was concluded that Cabergoline could be a safe and effective therapeutic alternative for chronic pain in endo- metriosis resistant to standard care, accord- ing to a pilot study. Larger randomized trials are needed to confirm these findings DiVasta et al. [60] Page 9 of 19 Shah et al. Future Journal of Pharmaceutical Sciences (2024) 10:35 Table 1 (continued) Phase Study design No of participants Eligibility criteria Arms of the study Study findings Inference Study Phase not applicable A prospective, rand- omized, parallel-assign- ment clinical trial to study the effect of administra- tion of GnRH agonist before in vitro fertilization to observe fertilization rate and pregnancy rate in endometriosis patients 180 participants Patients with infertility, endometriosis stage 1 Intervention: Leupro- lide (single injection of 3.75 mg every 28 days) Procedure: In vitro fertili- zation (IVF) The use of GnRH agonist resulted in a decrease in Follicular fluid cytokines in women compared to those who did not receive this regimen. However, no significant improve- ment took place in terms of embryo quality, rate of implantation, or rate of pregnancy Low follicular fluid cytokine levels along with high rates of implantations were noticed in sub- jects receiving GnRH agonist for the dura- tion of 3 months, with no significant difference in pregnancy and implantation rate Kaponis et al. [61] Page 10 of 19Shah et al. Future Journal of Pharmaceutical Sciences (2024) 10:35 density (BMD) as compared to Busrelin acetate. How - ever, compared to Busrelin acetate, a higher instance of genital bleeding and hot flushes within these patients was noticed with Dienogest highlighting its concern. This was the reason due to which this trial had to be suspended to avoid complications in these patients [62]. Due to the safety concerns occurring in conven - tional agents, it leads to negative therapeutic effects and it has been proposed that they be monitored care - fully during treatment and if they pose any risk to the patients, the trial should be terminated immediately. Also, novel drugs which are safer and more tolerable by the patients are required to prevent complications from occurring in them. Herbal therapy for endometriosis Epigallocatechin Gallate (EGCG) Epigallocatechin-3-gallate (EGCG) is the main constitu - ent of green tea due to which it can display its potency in cancer and endometriosis [64]. This herb has already been shown to possess anticancer and anti-oxidative properties. However, its effects in endometriosis were also evaluated by several researchers in endometriosis. It was shown to reduce inflammation by suppressing the release of NF-κB  along with mitogen-activated pro - tein kinase 1 (MAPK-1) in the endometrial lesions [55]. However, sufficient investigations have not been carried out as of yet to underline the exact mechanisms of EGCG through which it can cure endometriosis. The preclini - cal testing of EGCG in endometriosis was done by Ricci and co-workers in which they observed that treatment with EGCG inhibited the development of endometrial lesions along with decreasing the size of their lesions. It was able to modulate cellular proliferation, decrease the blood circulation to and from the endometrial lesions, and enhance the process of apoptosis [65]. Curcumin It is the active ingredient of commonly occurring tur - meric which has anti-inflammatory, anti-oxidative, and anti-proliferative properties [26, 66]. It can also block the actions of vascular endothelial-derived growth fac - tor (VEGF) within the endometrial cells of the rats sug - gesting its effects as anti-angiogenetic agents as VEGF is crucial for endometrial blood vessels to grow further and proliferate [58]. Furthermore, it is able to decrease the levels of IL-6, IL-8, and NF-κB in human endometrial stromal cells (Fig.  4). Hence due to all these beneficial properties, it has been suggested that curcumin may also be employed as a potential therapeutic agent for endo - metriosis [26]. Ginsenoside Rg3 This is a Chinese traditional herb and is the active com - ponent of ginseng which originates from the plant genus Panax. Preclinical findings have revealed the ability of this herb in reducing the endometrial lesion size in rats [67]. Its main actions include anti-oxidative and anti- inflammatory activities [26, 59]. In addition to this, this herb can also repress the angiogenesis process by inhib - iting the VEGF-mediated  formation of blood vessels suggesting its efficacy in reducing endometriosis [60]. Furthermore, a study carried out by Huang et  al. found that Ginsenoside Rg3 reduced inflammation by repres - sion of NF-κB and TNF-α in ectopic endometrial cells and also modulated apoptosis by regulating the expres - sion of caspase 3 and inhibiting VEGF-mediated angio - genesis [68]. Puerarin It is the major active ingredient of Gegen which is extracted from the Chinese medical herb Radix puerariae and falls in the category of phytoestrogens but possesses a weak estrogenic effect. They have sown to attach to estrogenic receptors and compete with 17β-estradiol (E2) thereby inhibiting the production of estrogen (Fig.  4). Its probable mechanism in endometriosis is its ability to suppress the vascularization of the endometrial cells by estrogen as it blocks the synthesis of estrogen through repression of the expression of aromatase cytochrome P450 (p450arom) in the endothelial stromal tissues [62–65]. When preclinical analysis was carried out, it suggested that it could influence and inhibit the inflam - matory microenvironment of the endometrial tissue in rats [32]. Resveratrol Resveratrol is also a phytoestrogen that is derived from grapes, wine, peanuts, etc. It has been identified to act against the progression of endometriosis due to its effects of anti-inflammation, via the repression of prostaglandin synthesis along with the modulation of apoptosis [69]. It has the ability to influence the estrogenic receptors (ER1 and 2) and has a mixed mechanism of action i.e., agonist and antagonist [67]. In addition to this, it has also been shown to regulate various pathways associated with cel - lular maturation and death such as MAPK, protein kinase B (Akt), protein kinase C, and peroxisome proliferator activated receptor-gamma (PPAR-ϒ) [70–72]. Apigenin Apigenin belongs to the category of flavonoids and is found in parsley, celery, oranges, wheat sources, etc. It possesses, anti-inflammatory, anti-proliferative, and Page 11 of 19 Shah et al. Future Journal of Pharmaceutical Sciences (2024) 10:35 anti-oxidant properties [73, 74]. Suou et  al. in a study to undermine the effects of apigenin in endometriosis observed that it reduced inflammation via suppress - ing protein expression and regulating the levels of IL-8 and TNF-α (Fig.  4) [75]. Recently conducted studies also revealed its effect in acting through binding with the progesterone receptors (PR) behaving as a probable phyto-progestin [76]. It was also shown to correct endo - metriosis symptoms such as pelvic pain, dysmenorrhea, infertility, etc. [77]. β‑Caryophyllene It belongs to the category of sesquiterpenes and is the active ingredient of essential oils which are derived from spices and food plants and is an effective anti-inflamma - tory herb in  vivo and was found to correct endometrial symptoms and infertility in adult rats [78, 79]. It was shown to mediate the inflammatory response by regu - lating their markers such as IL-1β, TNF-α, and toll-like receptors-4 (TLR-4) and angiogenesis by VEGF regula - tion. Recent findings also suggest its ability to block the generation of ROS through the MAPK pathway [74, 80]. Genistein It is an iso-flavonoid which is extracted from soy. It has strong Phyto-estrogenic actions and has been demon - strated both in vivo and in vitro and has been indicated in the treatment for endometriosis [81]. Genistein was shown to limit the progression of endometrial carcinoma in adult women as it regulated the process of angiogen - esis within the endometrium and apoptosis [82]. Addi - tionally, it can modulate the estrogenic receptors (ER) to regulate the release of estrogen and the process of angio - genesis occurring due to it. Furthermore, it can regulate inflammation by mediating the release of IL-6 and TNF-α [81]. Xanthohumol It is the active ingredient of Humulus lupulus L. and pos- sesses a variety of actions including anti-angiogenetic, anti-inflammatory, and anti-proliferative effects. Inflam - matory mediators such as NK-κβ, IL-1, Akt etc. can be regulated due to this herb [74, 83]. Herbal decoction method These methods are commonly employed in China to treat a variety of gynecological disorders such as endo - metriosis since 1983 [84]. Certain examples of these

include Qu Yi Kang (QYK), Yi Wei San (YWS), Xiaochaihu decoction (XCHD), Huoxue Xiaoyi (HX), and Xuefu Zhuyu (XZD) decoction methods based on their inventors [84]. Investigations into this have shown that XZD may relieve the symptoms of endometriosis, such as dysmenorrhea and ectopic lesions, and improve the issues of infertility in women and has resulted in greater efficacy of about 90% in the past times [84, 85]. Furthermore, XCHD has been shown to reduce the lev - els of estradiol (E2) levels, aromatase enzymes and also modulate the inflammatory mediator synthesis through the blockade of the COX-2 enzyme [85]. Other methods of decoction include Cai Shi Nei Yi Fang, Neiyi Zhitong, Huazhuo Jiedu Huoxue, and Juan Tong Yin etc.[86]. In a study carried out by Ding et  al. involving 80 patients wherein they compared the effects of Chinese traditional medicine and hormonal therapy (12.5  mg mifepristone orally each day) for Endometriosis. They observed that Chinese traditional medicine had a greater pregnancy rate (52.5%, 21/40) than hormonal therapy (37.5%, 15/40) within a 12-month period of follow-up and equivalent therapeutic effect to hormonal therapy suggesting a better potency of herbal therapy. Moreover, there were no SAE’s associated with herbal therapy and the results of renal and hepatic profile parameters proved that herbal therapy was well tolerated by all the patients [87]. This proves the long-standing efficacy as well as safety of herbal medicine to treat Endometriosis. Additionally, Zhao et  al. carried out a study in which they compared the effects of Chinese herbal medicine and western medicine by the means of a randomized controlled trial in 208 patients (106 in Chinese herbal medicine group and 102 in the western medicine group). Patients in the western medicine group were treated with a GnRH agonist or gestrinone, whereas patients in the Chinese medicine group were treated with agents including Modified Guifu Decoction, Radix Aconiti lat - eralis Preparata, Ramulus Cinnamomi, Radix Linderae, Rhizoma Sparganii, Rhizoma Curcumae, Spina Gledit - sia, Radix Salviae Miltiorrhizae, etc. For the patients in the Chinese medicine group, the mean time following surgery to achieve the first pregnancy was significantly shorter than for the patients in the Western medicine group (t = -2.09; P = 0.04). A statistically significant dif - ference existed between the 2 groups in terms of safety observed as after the treatment follow-up period, the western medicine group had increased ADRs such as fever, sweating, colpoxerosis, hypaphrodisia, weight gain, insomnia, irregular bleeding, headache, acne, and bone pain, while the patients in the Chinese medicine group only complained of occasional stomach pain that was immediately lowered after modifying the herbal remedies and dosages (83.3% vs. 9.4%, P < 0.01) [88]. Herbal combination therapies were associated with improving pregnancy rates, reducing adverse events and inhibiting the growth of endometrial tissues in addition to decreasing inflammation in patients. Therefore, com - bination therapy comprising of certain herbs may prove Page 12 of 19Shah et al. Future Journal of Pharmaceutical Sciences (2024) 10:35 to be beneficial in treating Endometriosis compared to conventional therapies. Furthermore, they have shown improvements in sub-populations of endometriosis patients including infertility patients, pre-menopausal syndromes, menstrual cycle irregularities, autoimmune disorders, etc. in terms of better hormonal balance res - torations, ovulation induction, lowering inflammation proving their efficacy. The major herbal agents discussed in the present review such as curcumin, EGCG, Gen - istein, β-Caryophyllene, etc., have shown limited adverse events in comparison with conventional therapy in terms of gastric disturbances including diarrhea, stomach upset, gastric irritation, etc. which can be easily managed with supportive treatment thereby enhancing their safety profile. In addition to this, their low cost of therapy adds to their benefit in treating Endometriosis. Herbal therapy has evolved over the recent times due to their offered advantages in the studies discussed above and other factors such as low cost, ease of convenience of preparing, reduced side effects and increased bioavail - ability. However, several additional investigations and clinical trials need to be conducted to evaluate efficacy and safety of different combinations of herbal therapies in Endometriosis which may also lead to the discovery of novel therapeutics to combat the disease effectively. Preclinical and clinical trial data of Herbal novel therapy in endometriosis The current ongoing preclinical trials in which the inves - tigations into the effects of herbal medicine to treat endo- metriosis are carried out are highlighted in Table 2. Preclinical trials Completed clinical trials There are a relatively limited number of clinical studies carried out to evaluate the safety as well as efficacy of herbal medicine against endometriosis. Phase-I rand - omized, placebo-controlled trial was carried out in 185 participants to gain idea on the potency of green tea extract in endometriosis in which the effects of green tea or Epigallocatechin-3-gallate  were compared with a placebo in order to assess its response. The investigators found that green tea extract displayed anti-angiogenetic, anti-fibrotic, and anti-proliferative properties which led to beneficial outcomes in lowering the progression of endometriosis and was tolerable by the patients suggest - ing its importance [91]. Similarly, a relatively same type of clinical trial was performed to evaluate the potency of garlic in endome - triosis. A total of 120 participants were recruited and one cohort was administered garlic tablets, while the other was given a placebo after which the response toward therapy was observed. It was noted that the patients that were receiving garlic therapy showed improvements in pain and statistical tests also showed its significance which concluded that herbal therapy can provide symp - tomatic relief also in addition to preventing the course of progression of endometriosis [92]. Ongoing clinical trials Table 3 enlists the various investigations that are pres - ently ongoing to investigate the effects of herbal therapy in endometriosis. Future prospects and opportunities Up till now, the treatments under existence only aim to regulate the hormonal levels in the body and provide relief from symptoms of endometriosis such as pain, dryness, infertility, etc. However, no specific treatments are available that can cure endometriosis completely or reduce its course of progression into its more severe forms. They only aim to suppress ovulation or alter the levels of hormones such as estrogen and progesterone in the body. Thus, there is a need to develop individualized regimens pertaining to specific patients to lower the inci - dences and recurrences of endometriosis [93]. Therefore, herbal medicines can prove to be a means to develop novel therapeutics to be given to endometriosis patients as many drugs have shown potent effects in decreasing the size of endometrial lesions and reducing inflamma - tion within them [81]. Herbal drugs are pleiotropic agents meaning they have multiple mechanisms of actions such as anti-oxidative anti-inflammatory, anti-angiogenetic, estrogen-modulating, analgesic, etc., which could resolve pelvic pain complaints of the patient along with lower - ing endometrial inflammation by blocking the release of inflammatory markers and protection from ROS species. By this, they can act as curative as well as symptomatic relief-providing agents [94]. Also, the improved safety and tolerability profile along with reduced cost of therapy makes them beneficial candidates over the conventionally available drugs presently in the market [84, 95]. Further- more, recent data suggests that medicinal cannabis as a dietary intervention may have effects in treating Endo - metriosis as it acts through various mechanisms such as suppressing inflammation, alleviating bloating, and act - ing as a painkiller. However, it has not fully been studied and additional research into this can be fruitful [96, 97]. Herbal therapy can also be used to induce pregnancy in an individual who cannot conceive due to endometrio - sis and can be utilized as a safer approach compared to conventionally existing drugs with almost no harm to the individual or the fetus [98]. Only further and larger number of studies need to be conducted in a similar manner to evaluate the extent of the benefit that herbal therapy provides or reducing the likelihood of developing Page 13 of 19 Shah et al. Future Journal of Pharmaceutical Sciences (2024) 10:35 Table 2 A table showing the animal preclinical trials conducted to evaluate the potency of herbal medicine in endometriosis Sr. No Study objectives Study design Arms of the study Study findings Study 1 A study in order to find the association between the Ginsenoside Rg3 effect on endometrial growth and the PI3K/ Akt/mTOR signaling pathway modulated by VEGFR-2 The rats were allocated on the basis of randomization into 5 groups which were treated with ginsenoside Rg3 and sacrificed 21 days post drug treat- ment. Measurement of the endometrial volume was carried out and the inhibi- tory rate was calculated. Serum estradiol (E2) and progesterone (P) levels were analyzed by Electrochemiluminescence Immunoassay (ECLI). Using immunohisto- chemical techniques, the protein expres- sion of VEGF and VEGFR-2 was evaluated within the endometrium Intervention 1: Ginsenoside Rg3 (5 mg/ kgBW/d) Intervention 2: Ginsenoside Rg3 (10 mg/ kgBW/d) Intervention 3: Gestrinone group (0.5 mg/kgBW/d) Intervention 4: Control group (10 mL/kg BW/d of 0.5% Carboxymethyl cellulose sodium) CMC-Na Intervention 5: Ovariectomized group (10 mL/kgBW/d of 0.5%CMC-Na) It was observed that a dose-dependent suppression of endometrium size in rats in comparison to control group occurred. A down-regulation of the expression of VEGF and VEGFR-2 was also noticed in Ginsenoside Rg3 group Cao et al. [67] 2 A study to evaluate the effect of EGCG in mice-model of endometriosis The potential for EGCG as an anti-angio- genesis agent was investigated in mice suffering from endometriosis. Trans- plantation of endometrium was done in mice and they were divided into 3 groups to receive treatment for 4 weeks. Endometrial growth was measured through non-invasive in vivo imaging (IVIS). Post-treatment, the bioavailability, anti-oxidative and anti-angiogenesis effects were measured Intervention 1: Dulbecco phosphate buffered saline Intervention 2: Vitamin E (20 mg/kg) Intervention 3: EGCG (50 mg/kg) A significant reduction in the endometrial lesion size was observed in the group treated with EGCG from 2nd to 4th week of drug treatment. However, they failed to show effect on Ovarian follicles and uterine endometrial glands Xu et al. [89] 3 A study to investigate the potency of puerarin in endometriosis (EMT) model rats and to find the probable mechanisms of action The animals were allocated into 5 groups and endometriosis was induced surgically by auto-transplantation of endometrial tissues. Serum estradiol (E2) and prosta- glandin E2 (PGE2) levels were analyzed and the dose of administration was calcu- lated. Genes and proteins of the endome- trial tissues were analyzed by polymerase chain reaction (PCR) and immunohis- tochemistry (IHC). Based on the results, appropriate inferences were made Puerarin and Raloxifene (RLX) both mixed with CMC prorata after which the animals were allocated into five groups were respectively administered drug treatment for 4 weeks Intervention 1: low-dose group (0.1% CMC and 5 mg/kg puerarin) Intervention 2: 0.1% CMC and 20 mg/kg puerarin) Intervention 3: 0.1% CMC and 80 mg/kg puerarin) Intervention 4: positive control group (Raloxifene hydrochloride) RLX 10 mg/kg Intervention 5: Control group (CMC) It was observed that Puerarin reduced the concentrations of E2 and PGE2 and also hindered the maturation of endometrium tissues by inhibiting the expression of aromatase cytochrome P450 (p450arom) and cyclooxygenase-2 (COX-2). Also, it modulated the metabo- lism of E2 by controlling the expression of the 17β-hydroxysteroid-2 (17β-hsd-2) enzyme of the endometrial tissues Surrey et al. [58] Page 14 of 19Shah et al. Future Journal of Pharmaceutical Sciences (2024) 10:35 Table 2 (continued) Sr. No Study objectives Study design Arms of the study Study findings Study 4 A clinical study to assess the effect of β-caryophyllene on endometriosis along with fertility status in adult female rats along with their roles in reproduction Fragments of endometrium were implanted in the peritoneal cavity of the animals to induce endometriosis within them. Their growth was measured from baseline and after 4 weeks. Alloca- tion was carried out of the animals into 2 groups and they were given drug therapy for a duration of 21 days Intervention: β-caryophyllene (10 mg/kg or 30 mg/kg) Control: Vehicle It was observed that β-Caryophyllene was able to hinder the maturation of endometriotic tissues 52.5% in rats compared with controls whereas β-caryophyllene led to apoptosis in the epithelium of the endometrial lesions Abbas et al. [90] Page 15 of 19 Shah et al. Future Journal of Pharmaceutical Sciences (2024) 10:35 Table 3 Currently ongoing clinical studies for the evaluation of herbal therapy in endometriosis NCT number, current phase Study design Eligibility criteria Arms of the study Primary endpoints NCT04493476, Phase II A double-blind, prospective and placebo-regulated clinical trial to assess the response of combination therapy of Chinese herbal medicine and curcumin to lower the symptoms of endometriosis Women having a confirmed diagnosis of endometriosis, women aged 18–45 years (reproductive age), no allergy to the ingredients of the intervention or the control Intervention: Daily dietary dosing of Chinese medicine and curcumin given in the form of 800 mg capsules Control: Placebo (Invo capsules given in daily dosing) The overall benefit in the symptoms of the disease NCT03016039 A randomized, parallel assignment study of curcumin supplementation for endometriosis Age above 18, patient with a diag- nosis of pelvic inflammatory disease/ Tubo ovarian abscess, surgical wound infection, endometritis Intervention: Curcumin supplementa- tion Change in the Levels of C-reactive protein, change in the levels of white blood cells NCT03875261, Phase II A randomized, single-group assign- ment study to examine the response of the effect of Cannabinoid (CBD) on pain experienced by endometrio- sis patients Women falling in the age group of 18 and 40, having a confirmed diagnosis of endometriosis with clinical inves- tigations, suffering from symptoms of pain, dysmenorrhea, etc. Intervention: Participants adminis- tered cannabinoid derivates dosing between 1 and 12 puffs. Each puff contained 2–7 mg of delta-9-tetrahy- drocannabinoland 2–5 mg of can- nabidiol Pressure threshold in hypogastrium that induces pain NCT02676713, Phase II A randomized, prospective, multi- centric study to evaluate the efficacy of Decoction (Chinese herbal medi- cine to treat infertility) in endome- triosis Women having a clinical diagnosis of endometriosis, endometriosis fertil- ity index (EFI) score greater than 4 points, firstly undergoing laparo- scopic surgery, the female of repro- ductive age (18–45 years) Intervention: Decoction (Bupleurum 10 g, Cyperus 10 g, Salvia miltiorrhiza 20 g, Red peony 10 g, etc.) Placebo: Combination of maltodex- trin, lactose, edible pigment, and taste masking agent Pregnancy rate to an extent of six menstrual cycles NCT04150406, Current phase not given A multicentric, randomized clinical trial to evaluate the potency of Flexo- fytol in endometriosis Women of reproductive age (18–51 years), diagnosed with endo- metriosis, moderate to severe pelvic pain Intervention: Flexofytol (Curcumin 42 mg 2 capsules administered for 4 months) Control: Placebo Alteration in the baseline pain score NCT number not given A randomized, multicentric clinical trial to evaluate the effect of Ashoka- rishta, Ashwagandha Churna, and Praval Pishti in patients suffering from menopausal syndrome Females of age 40–55 years, suffer- ing from amenorrhea for a period of greater than 12 months, were will- ing to comply with the study require- ments, providing written consent to be included in the study Intervention: Ashokarishta (25 mL daily), Ashwagandha (3 g twice daily with milk), Praval Pishti (250 mg twice daily) Control: Placebo Improvement in the Menopausal rating scale (MRS), Incidences of adverse events (AEs) Page 16 of 19Shah et al. Future Journal of Pharmaceutical Sciences (2024) 10:35 endometriosis and curing it completely. Herbal therapy trials were limited in number, while trials for conven - tional therapy were found to be widely available. There - fore, when the results of trials for herbal therapy become available, they will strengthen the point discussed in this manuscript regarding the comparison of safety and effi - cacy of conventional and herbal medicine.

The currently existing conventional therapies are only aimed at inhibiting the hormonal parameters of the patient and providing symptomatic relief from symp - toms such as pelvic pain, vaginal dryness, etc., but can - not completely cure the disease. Conventional therapy also possesses several other limitations such as increased cost of therapy, risk of recurrence of endometriosis, lim - ited safety and efficacy profile, and tolerability issues. On the other hand, herbal therapies extracted from natural sources have shown promising effects in delay - ing the course of endometriosis progression and have better effects compared to conventional therapy along with improved tolerability and almost no adverse events to the patients making them a perfect candidate for the treatment of endometriosis concerning to efficacy, safety, and tolerability. The comprehensive studies data indicate that conventional therapy results in unsatisfactory thera - peutic outcomes, disease recurrence, and an increase in the development of ADRs, whereas herbal combination therapy acts through multiple mechanisms, resulting in better clinical therapeutic outcomes and less ADRs, highlighting their benefit in terms of efficacy and safety in treating endometriosis. However, the number of pre - clinical and clinical trials investigations into this context is limited which is why additional studies are crucial to identify the potency of herbal drugs treating endometrio- sis effectively. Abbreviations 17β-HSD1 17-Beta hydroxysteroid dehydrogenase ADRs Adverse drug reactions AEs Adverse events Akt Protein kinase B AMH Anti-mullein hormone BMD Bone mineral density BPA Bisphenol-A CBD Cannabinoid CHCs Combined hormonal contraceptives CMC-Na Carboxymethyl cellulose sodium COCs Combined oral contraceptives CRP C-reactive protein E2 17β-Estradiol ECLI Electrochemiluminescence Immunoassay EFI Endometriosis fertility index EGCG Epigallocatechin Gallate EMT Endometriosis model rats ER1 and ER2 Estrogenic receptors 1 and 2 FSH Follicle-stimulating hormone GnRH Gonadotrophin-releasing hormone HPA Hypothalamic-pituitary axis HX Huoxue Xiaoyi IHC Immunohistochemistry IL Interleukin IVF In vitro fertilization IVIS Non-invasive in vivo imaging LH Luteinizing hormone MAPK-1 Mitogen-activated protein kinase-1 MRS Menopausal rating scale NF-κβ Nuclear factor-kappa beta NSAIDs Non-steroidal anti-inflammatory drugs P450arom Aromatase cytochrome P450 PCR Polymerase chain reaction PGE2 Prostaglandin E2 PKC Protein kinase C PPAR-ϒ Peroxisome proliferator activated receptor-gamma PR Progesterone receptors QOL Quality of life QYK Qu Yi Kang RLX Raloxifene hydrochloride SAE Serious adverse events SERMs Selective estrogen receptor modulators SPRMs Selective progesterone receptor modulators TLR-4 Toll-like receptors-4 TNF-α Tumor necrosis factor-alpha USA United States of America VEGF Vascular endothelial-derived growth factor XCHD Xiaochaihu decoction XZD Xuefu Zhuyu YWS Yi Wei San

The authors are grateful to Prof. Gaurang B. Shah, Department of Pharmacol- ogy, L. M. College of Pharmacy, Ahmedabad, Gujarat, India, for kind support and guidance in manuscript preparation. The authors also extend their appreciation to the L. M. College of Pharmacy, Ahmedabad, India, for provid- ing continuous library and resource support throughout the literature survey and data collection. Disclosure The authors have no financial or non-financial interest to disclose. All the investigators take responsibility for the integrity of the data and the accuracy of the data analysis. All data from clinical trials of the use of herbal therapy toward the treatment of endometriosis (https:// clini caltr ials. gov/). Author contributions BD, SB, HR and MS contributed to manuscript first draft preparation and subsequent editing, literature and data collection, data analysis, figures and diagram conception as well as designing and writing the manuscript. AK and NP contributed to topic conception, design of content and skeleton, manuscript draft review and editing, figures and diagram conception, overall monitoring, and guidance throughout the study duration. All authors have read and approved the final manuscript. Funding This review did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Availability of data and materials The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request. Declarations Ethics approval and consent to participate Not applicable. Consent for publication The authors declare no conflict of interest. Page 17 of 19 Shah et al. Future Journal of Pharmaceutical Sciences (2024) 10:35 Competing interests The authors declare that they have no competing interests. Author details 1 Gujarat Technological University, Ahmedabad, Gujarat, India. 2 Department of Pharmacology, L. M. College of Pharmacy, Opp. Gujarat University, Navrang- pura, Ahmedabad, Gujarat 380009, India. 3 Department of Pharmaceutical Chemistry and Quality Assurance, L. M. College of Pharmacy, Opp. Gujarat University, Navrangpura, Ahmedabad, Gujarat 380009, India. Received: 5 November 2023 Accepted: 26 February 2024

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