Natural Products Targeting Oxidative Stress–Inflammation Crosstalk in Endometriosis

ABSTRACT

Problem

Endometriosis is a chronic, estrogen‐dependent inflammatory disorder marked by ectopic endometrial‐like tissue growth, resulting in pelvic pain, infertility, and significant declines in quality of life. Despite extensive research, current therapies remain largely symptomatic and are often associated with recurrence, hormonal adverse effects, and compromised fertility outcomes. Growing evidence indicates that oxidative stress, chronic inflammation, mitochondrial dysfunction, altered immune surveillance and metabolic dysregulation are central drivers of lesion establishment and progression. However, these interconnected mechanisms are often examined in isolation, limiting translational progress.

Method of Study

We provide a comprehensive, integrative analysis of the molecular and cellular pathways underlying endometriosis, with particular emphasis on oxidative stress–inflammation crosstalk, signalling cascades supporting lesion survival, and emerging metabolic and mitochondrial targets. By critically synthesising recent experimental, preclinical, and clinical findings, this review highlights mechanistic overlaps that may explain therapeutic resistance and disease recurrence. Furthermore, it evaluates novel pharmacological and nutraceutical interventions targeting redox imbalance, inflammatory mediators, and intracellular signalling pathways, thereby expanding the conceptual framework beyond conventional hormonal suppression. Rising global endometriosis prevalence and its socioeconomic burden necessitate a shift from purely symptomatic management to mechanism‐driven therapeutic strategies.

Results

This review addresses that gap by consolidating dispersed evidence into a unified mechanistic perspective, identifying promising translational targets, and proposing future research directions. The insights provided will help in creating safer, fertility‐preserving and more durable treatments. Thus, we categorise natural products by: (1) translational development stage (in vitro to clinical candidate); (2) regulatory pathway (dietary supplement, herbal medicine, or pharmaceutical); and (3) clinical context (e.g., pain control, recurrence prevention, or fertility preservation). Conclusion: This structured, clinically‐oriented framework distinguishes the present synthesis from mechanistic reviews and serves to guide both future research design and rational integration of natural products into endometriosis therapeutic strategies.

Abbreviations

ANG‐1

Angiopoietin‐1

ANG‐2

Angiopoietin‐2

AYUSH

Ministry of Ayurveda, Yoga & Naturopathy, Unani, Siddha, and Homeopathy

CA‐125

Cancer Antigen 125

CFDA

China Food and Drug Administration

CHM

Chinese Herbal Medicine

COX‐1

Cyclooxygenase‐1

COX‐2

Cyclooxygenase‐2

EGCG

Epigallocatechin‐3‐gallate

EMA

European Medicines Agency

ER

Estrogen Receptor

ERK

Extracellular Signal‐Regulated Kinase

ESC

Endometrial Stromal Cells

ET

Endometrial‐like Tissues

GMP

Good Manufacturing Practice

GnRH

Gonadotropin‐Releasing Hormone

GnRHa

Gonadotropin‐Releasing Hormone Agonist

HIF‐1α

Hypoxia‐Inducible Factor‐1 Alpha

ICAM‐1

Intercellular Adhesion Molecule‐1

IL

Interleukin

IL‐10

Interleukin‐10

IL‐1β

Interleukin‐1 Beta

IL‐6

Interleukin‐6

IL‐8

Interleukin‐8

IND

Investigational New Drug

iNOS

Inducible Nitric Oxide Synthase

JNK

c‐Jun N‐terminal Kinase

LPS

Lipopolysaccharide

MAPK

Mitogen‐Activated Protein Kinase

MC

Mesothelial Cells

MCP‐1

Monocyte Chemoattractant Protein‐1

MD

Müllerian Ducts

MDA

Malondialdehyde

MMP

Matrix Metalloproteinase

MMP‐2

Matrix Metalloproteinase‐2

MMP‐9

Matrix Metalloproteinase‐9

MPO

Myeloperoxidase

NF‐κB

Nuclear Factor Kappa‐Light‐Chain‐Enhancer of Activated B Cells

NO

Nitric Oxide

OCP

Oral Contraceptive Pill

OS

Oxidative Stress

PGE2

Prostaglandin E2

PI3K/AKT

Phosphoinositide 3‐Kinase/Protein Kinase B

PK

Pharmacokinetics

PMDA

Pharmaceuticals and Medical Devices Agency (Japan)

PR

Progesterone Receptor

RCT

Randomized Controlled Trial

RM

Retrograde Menstruation

ROS

Reactive Oxygen Species

RTK

Receptor Tyrosine Kinase

SAC

S‐Allyl‐Cysteine

SMN

Silymarin

TCM

Traditional Chinese Medicine

TIE‐2

Tyrosine Kinase with Immunoglobulin‐like and EGF‐like Domains 2

TIMP‐1

Tissue Inhibitor of Metalloproteinases‐1

TNF‐α

Tumor Necrosis Factor‐Alpha

VCAM‐1

Vascular Cell Adhesion Molecule‐1

VEGF

Vascular Endothelial Growth Factor

VEGF‐C

Vascular Endothelial Growth Factor‐C

VEGFR2

Vascular Endothelial Growth Factor Receptor‐2

VK2

Vaginal Keratinocyte Cell Line

XN

Xanthohumol

1. Introduction

Endometriosis is an oestrogen‐dependent benign gynaecological disorder defined by ectopic proliferation and growth of endometrial‐like tissues outside the uterine cavity [1]. This debilitating condition significantly impairs a patient's long‐term quality of life and general well‐being. Primary clinical manifestations include chronic pelvic pain, infertility, and elevated ovarian cancer risk [2]. Approximately 5%–10% of women within the reproductive age range suffer from this disorder. Its complex pathophysiology is consistently characterized by systemic inflammation, pelvic pain, and infertility [3]. This endometrial tissue in patients with endometriosis demonstrates intrinsic survival characteristics that enable its proliferation and growth outside the uterine cavity. This pathogenic process induces chronic inflammation, angiogenesis, proliferation, reactive oxygen species (ROS) generation, and severe pelvic pain [4]. Malignant transformation of endometriosis is a rare event occurring in < 1% of cases [5]. Angiogenesis is a critical factor in endometriosis development and a leading pharmacological target [6]. Clinicians in China and other Asian nations frequently employ Chinese herbal medicine (CHM) for endometriosis management [7]. However, further large‐scale randomized trials relating to anti‐endometriosis and anti‐angiogenic effects are required [8].

Therapeutic strategies for endometriosis include expectant management, pharmacological (hormonal) therapy, and surgery [9]. Pharmacological protocols include oral contraceptives, GnRH‐a, and progestins. These agents reduce estrogenic endometrial activity to suppress menstruation [9]. GnRH‐a and GnRH‐ant administration necessitates monitoring for hypoestrogenic adverse effects. Observed sequelae include vasomotor symptoms (hot flashes) and skeletal demineralization [10, 11]. However, pharmacological treatment is suppressive in nature [9]. Long‐term administration produces notable side effects [12]. Surgical intervention remains standard for endometriosis, yet reports demonstrate variable long‐term efficacy [13, 14].

Phytomedicine historically provided therapeutic interventions for human pathologies [15]. Plant‐derived extracts constitute complex, multi‐constituent systems; individual component synergy confers significant therapeutic efficacy [16]. Several plants have been shown to have beneficial effects in the treatment of endometriosis, including Pueraria flower, black garlic, apigenin, green tea, xanthohumol, milk thistle and pine bark [17]. These botanical extracts demonstrate enhanced efficacy and a superior adverse event profile compared to conventional endometriosis therapies [18]. This review elucidates botanical agent mechanisms in endometriosis therapy. It presents a comprehensive analysis of herbal therapies in endometriosis. It emphasizes their anti‐angiogenic potential, an underexplored therapeutic area. This analysis systematically correlates phytoconstituents with key pathological pathways: Inflammation, oxidative stress, and aberrant cell proliferation. The review highlights multi‐target mechanisms of herbal compounds versus conventional single‐target therapies. It bridges preclinical findings and clinical applicability. It identifies limitations in current evidence. It proposes standardized phytomedicines as safer long‐term therapeutic alternatives. This work clearly offers a novel therapeutic framework for integrating herbal medicine into endometriosis management.

2. Methods

We searched for articles published from 2001 to 2025. The literature search utilized multiple online databases: ScienceDirect, Google Scholar, MDPI, PubMed, ResearchGate, Nature, Frontiers, Wiley Cancer Science and Dovepress. Keywords for the review included: Endometriosis, herbal treatment, herbal ingredients, biomarkers, herbal medicine, phytotherapy, angiogenesis, oxidative stress, inflammation, and phytoconstituents. The search encompassed English‐language articles on endometriosis treatment via botanical extracts, including in vivo, in vitro, and human clinical trials.

3. Pathophysiology of Endometriosis

Endometriosis pathophysiology involves complex interactions between cellular and tissue environments. Proposed etiologic models include retrograde menstruation, circular dissemination, coelomic metaplasia, and Müllerian remnants [10, 19]. Beyond these theories, the key pathological processes that drive the disease are often the targets for herbal therapies. These include chronic inflammation, angiogenesis, and oxidative stress. Chronic inflammation is central to the pathogenesis of endometriosis [20]. Inflammation drives the progression of endometriosis through an inflammatory cascade [21]. Mediators upregulated in endometriosis include metalloproteinases, prostaglandins, cytokines, and chemokines. Specific inflammatory markers are elevated in the peritoneal fluid of affected individuals, including interleukin‐10 (IL‐10), IL‐6, IL‐8, COX‐2, VEGF, and TNF‐α [6]. ROS production modulates disease progression [22]. ROS promote activation of the nuclear factor‐κB (NF‐κB) pathway, a mechanism critical to disease initiation [18].

Angiogenesis is a multi‐step process involving the formation of new blood vessels. It is crucial during both embryonic development and postnatal life. Multiple signalling pathways govern angiogenesis. Vascular endothelial growth factor (VEGF) is upregulated by physiological stimuli, including inflammation and hypoxia [23]. The hypoxia‐inducible factor‐1 alpha (HIF‐1α)/VEGF pathway enhances endothelial cell activity [24]. This pathway drives endothelial cell proliferation and migration, facilitating the formation of new capillaries. Angiopoietin‐1 (ANG‐1) and Angiopoietin‐2 (ANG‐2) regulate the formation of new blood vessels from existing ones [25]. ANG‐1 promotes endothelial cell association and stabilizes vasculature, whereas ANG‐2 acts as a competitive antagonist, destabilizing blood vessel structure [26]. TIE‐2 receptor tyrosine kinase (RTK) is a key regulator in angiogenesis. Under stable conditions, ANG‐1 acts as an agonist for TIE‐2, causing stabilization [27]. ANG‐2 disrupts this stabilization, creating conditions conducive to VEGF‐driven endothelial cell functions [27]. Angiogenesis contributes to endometriosis. We must delineate the underlying regulatory mechanisms [23].

Oxidative stress (OS) is an imbalance between ROS production and antioxidant defense mechanisms [28]. Macrophages and apoptotic endometrial tissue induce OS in endometriosis [29]. This environment fosters tissue invasion, uncontrolled proliferation, angiogenesis and apoptosis evasion. Endometriotic lesions and tumour cells require a sufficient blood supply and protection from apoptosis to survive. This reliance links the proliferation of both endometriotic and tumour cells. Increased ROS production correlates with enhanced cell proliferation and the metastatic nature of tumour cells [30]. This relationship is similarly observed in the context of endometriosis. Augmented ROS production activates the mitogen‐activated protein kinase (MAPK) pathway, promoting cell proliferation [31]. This activation plays a critical role in the progression of endometriosis. ROS enhances NF‐κB activity in peritoneal macrophages, stimulating growth, angiogenesis, and inflammation in endometriotic cells. ROS‐driven inflammation characterizes endometriosis progression. OS‐mediated damage in endometriosis and tumour cells demonstrates the significant role of ROS in disease progression.

3.1. Retrograde Menstruation

John Sampson proposed the theory of ectopic endometrial cells in the 1920s. This theory is accepted as the primary hypothesis for the aetiology of endometriosis [30]. Ectopic endometrial cells are believed to originate from the uterus and travel through the fallopian tubes. They enter the peritoneal cavity during the menstrual cycle, leading to conditions such as ovarian endometriomas and pelvic endometriosis [30]. Women with endometriosis tend to have shorter cycle lengths and heavier menstrual flow. The retrograde menstruation theory does not account for endometriosis in premenarcheal girls, female foetuses, and male patients [10].

3.2. Vascular Dissemination

This theory, proposed by Sampson, was intended to explain the development of endometriosis [32]. Endometrial stromal or bone marrow‐derived cells traverse the bloodstream or lymphatic system to distant sites [32]. This mechanism facilitates extra‐pelvic endometriosis, manifesting as lesions in the lungs, liver and brain [32].

3.3. Coelomic Metaplasia

Iwanoff (1898) and Meyer (1924) proposed the coelomic metaplasia theory [33]. Endometriosis originates in situ via metaplastic transformation of cells, including peritoneal mesothelial cells and stem cells. Hormonal and immune factors drive this pathogenic transition. Supporting evidence includes mesothelial‐mesenchymal transitions [34] and genetic similarities [35]. The Müllerian remnant hypothesis complements this framework, explaining endometriosis in locations unaffected by retrograde menstruation [32].

3.4. Müllerian Remnants Theory

The Mullerian remnants theory holds that endometriosis can develop from remnants of embryonic tissue [32]. This helps explain why the disease can appear in individuals who have not yet started menstruating, such as foetuses and premenarcheal girls, as well as in rare cases of extra‐pelvic endometriosis, even in the absence of menstrual flow [32]. Figure 1 illustrates the scientific theories regarding the initiation and progression of endometriosis.

FIGURE 1.

Theoretical frameworks for the pathophysiology and pathogenesis of endometriosis. The schematic outlines four primary theories proposed to explain the development of ectopic endometrial tissue. (1) Retrograde Menstruation (RM): Sampson (1920s) proposed that menstrual blood refluxes through fallopian tubes. Viable cells subsequently implant in peritoneal cavity [36]. (2) Vascular Dissemination: Sampson proposed endometrial stromal/progenitor cell infiltration of hematologic or lymphatic systems. This facilitates dissemination to distant sites [37]. (3) Coelomic Metaplasia: Hormonal or inflammatory factors trigger metaplastic transformation of multipotent peritoneal mesothelial cells (MC) into endometrial‐like tissues (ET) [36]. (4) Mullerian Remnant Theory: Postnatal persistence of embryonic Mullerian duct (MD) cells allows differentiation into ectopic lesions during reproductive years [38]. ET, Endometrial‐like tissues; MC, Mesothelial cells; MD, Mullerian ducts; RM, Retrograde menstruation.

4. Conventional Therapies and Limitations

The conventional treatment strategy for endometriosis includes the use of pain management medication, hormone‐based treatments (such as oral contraceptives, progestins, and GnRH agonists/antagonists) and surgical excision or ablation of lesions; these approaches frequently provide symptomatic relief but are limited by adverse effects (e.g., hypoestrogenic symptoms, bone loss, mood changes), recurrence after treatment cessation, and incompatibility with immediate fertility goals [9]. Despite improvements in hormonal agents and minimally invasive surgical approaches, the recurrence rate of endometriosis remains as high as 40%–50% within five years, underscoring the need for more durable therapies [39]. Moreover, long‐term hormonal suppression is unsuitable for women actively pursuing pregnancy, creating an unmet clinical need for non‐hormonal adjunctive options [40].

In response to these limitations, herbal medicines and nutraceuticals are gaining attention for their multi‐targeted mechanisms, relative affordability, and patient acceptability [41]. Herbal and phytochemical therapies have been widely investigated as complementary options because many plant compounds target inflammation, OS, angiogenesis and aberrant cell survival pathways central to disease pathogenesis [42]. However, translation of promising preclinical results into clinical practice is constrained by several problems: Lack of standardized extracts and validated dosing regimens, poor bioavailability of some actives (e.g., apigenin) without advanced delivery systems, heterogeneous and often small clinical trials with short follow‐up, potential herb–drug interactions (notably with hormonal agents and anticoagulants), and persistent quality‐control/contamination concerns for some commercial products. There are safety and quality control challenges, including adulteration of herbal products with undeclared pharmaceuticals or heavy metals, as highlighted in recent pharmacovigilance reports [43]. Finally, the heterogeneity of patient populations and variability in herbal formulations complicate the interpretation of clinical outcomes and make meta‐analyses difficult [44]. Herbs function as supportive therapies; however, rigorous clinical trials and standardization must precede clinical adoption [45].

5. Rationale for Herbal Therapy

Endometriosis pathophysiology comprises chronic inflammation, angiogenesis, OS, hormonal dysregulation and apoptosis resistance. Single‐target pharmacotherapy fails to provide complete resolution [46]. Phytochemicals provide multi‐target regulation of these pathways [47]. For example, polyphenols such as apigenin inhibit NF‐κB and COX‐2, helping suppress prostaglandin production and the release of inflammatory cytokines [48]. At the same time, epigallocatechin gallate (EGCG) from green tea interferes with VEGF‐mediated angiogenesis and reduces fibrotic changes [49, 50]. Flavonoids such as apigenin provide strong antioxidant defence by scavenging ROS, which are elevated in endometriotic lesions [51]. This multi‐target approach aligns with the multifactorial nature of endometriosis and explains why herbs are increasingly investigated as complementary therapies [52].

Ethnopharmacological data support herbal interventions [53]. Ayurveda and Traditional Chinese Medicine (TCM) systems utilize herbs (e.g., Saraca asoca, Asparagus racemosus) and formulas (e.g., Gui Zhi Fu Ling Wan) to treat gynaecological disorders [54]. Modern pharmacological studies confirm that many of these herbs regulate estrogenic receptor activity, promote apoptosis of ectopic endometrial cells, and reduce oxidative and inflammatory stress [55]. Furthermore, their favourable safety profiles and patient acceptability make them attractive adjuncts to conventional hormonal or surgical treatments, particularly for women seeking fertility preservation or those intolerant to long‐term hormonal suppression [54]. Overall, the traditional use, scientific evidence, and preclinical studies support the use of herbs as complementary treatments for endometriosis.

6. Herbal Agents in Endometriosis Management

We systematically categorised herbal agents by translational evidence level using established drug development frameworks. We defined four stages. Stage 1 (in vitro evidence): Mechanistic data are limited to cell‐culture experiments and there is no validated animal model of endometriosis. Stage 2 (animal‐model evidence): In vitro findings correlate with in vivo rodent studies. Stage 3 (preliminary human data): Small‐scale observational studies or pilot trials yield early clinical signals. Stage 4 (clinically usable candidate): Randomised controlled trials (RCTs) demonstrate efficacy and safety data sufficient for clinical consideration. Table 1 summarises the translational stage classification of each agent.

TABLE 1.

Translational stage classification of natural products reviewed for endometriosis.

Compound	Current evidence level	Translational stage	Key evidence
Apigenin	In vitro only	Stage 1: In vitro evidence only	Inhibits ESC proliferation/apoptosis (in vitro); exhibits phytoprogestin activity. Lacks in vivo/human trial data [56].
Puerarin	In vitro + animal models	Stage 2: Animal‐model evidence	Rat models demonstrate lesion reduction and estrogen suppression; in vitro anti‐proliferative/anti‐angiogenic effects verified. Lacks human RCTs [57].
Xanthohumol	In vitro + animal models	Stage 2: Animal‐model evidence	BALB/c models demonstrate lesion regression; in vitro anti‐angiogenic/mechanistic properties confirmed. Lacks specific clinical trials [58].
Black Garlic (SAC)	In vitro + limited clinical	Stage 3: Preliminary human data	18‐patient study demonstrates dysmenorrhea/pain reduction; in vitro NF‐κB inhibition and in vivo anti‐inflammatory effects observed [59].
Pine Bark (Pycnogenol)	RCT clinical data	Stage 4: Clinically usable candidate	RCTs demonstrate reduced pain, cramps, and CA‐125; efficacy is comparable to GnRHa. No fertility/hormonal disruption observed [60].
Milk Thistle (Silymarin)	In vitro + animal models	Stage 2: Animal‐model evidence	Rodent models demonstrate silibinin‐induced lesion reduction. Lacks specific endometriosis RCTs; one 2022 RCT shows symptomatic benefit [61, 62].
Green Tea (EGCG)	In vitro + animal models	Stage 2: Animal‐model evidence	Preclinical studies demonstrate anti‐angiogenic, pro‐apoptotic, and anti‐proliferative effects. Lacks human clinical trials in endometriosis [63]

Abbreviations: CA‐125, Cancer Antigen 125; EGCG, Epigallocatechin‐3‐gallate; ESC, Endometrial Stromal Cells; GnRHa, Gonadotropin‐Releasing Hormone agonist; NF‐κB, Nuclear Factor kappa B; RCT, Randomized Controlled Trial; SAC, S‐Allyl‐Cysteine; TCM, Traditional Chinese Medicine.

6.1. Apigenin

Apigenin is a bioactive flavonoid found in parsley, oranges, chamomile, celery, and wheat [64, 65, 66, 67]. Clinical studies demonstrate efficacy in treating cancer, diabetes, and Alzheimer's [68]. Apigenin exhibits various biological activities, including antiproliferative, anti‐angiogenic, antioxidant and anti‐inflammatory properties [68, 69]. Adding apigenin to surgically obtained endometriotic stromal cells reduced protein expression and TNF‐α‐induced IL‐8 gene expression. The same group later showed that apigenin can inhibit TNF‐α‐induced cellular proliferation, mitigating chronic inflammation and mitogenic activity by reducing PGE2 expression and downregulating the NF‐κB pathway [52, 70, 71]. Apigenin exerts anti‐endometriotic effects in vitro by reducing cell proliferation and triggering both apoptosis (cell death) and cell cycle arrest [72, 73]. The cell death mechanism involves inhibiting JNK and ERK1/2 phosphorylation, disrupting mitochondrial membrane potential, and increasing pro‐apoptotic proteins such as Bax and cytochrome c [72]. Additionally, apigenin may function as a potential phytoprogestin, interacting with progesterone receptors (PR) to block increases in endometrial cell height and up‐regulate Hand2 transcription factor expression [74]. Therapeutic potential derives from established anti‐inflammatory, antiproliferative, and progestogenic activities. Despite promising laboratory results, apigenin's effectiveness has not yet been evaluated in preclinical animal models of endometriosis [75]. Apigenin binds to PR, mimicking endogenous progesterone [74, 76].

Apigenin improves the common symptoms of endometriosis, like pelvic pain, painful periods, and infertility [77]. We utilised endometrial stromal cells (ESCs) derived from human endometriomas [78]. Apigenin inhibits TNF‐α‐induced ESC proliferation [72]. Treatment reduced COX‐2 and PGE‐2 expression levels [77]. Endometriosis often presents with diminished endometrial receptivity secondary to progesterone resistance. Consequently, we investigated the progesterone‐regulated protein CRISP3 [79]. We compared endometrial CRISP3 levels in macaques with and without endometriosis [80]. Apigenin functions as an anticancer phytoprogestin [77]. Molecular assays demonstrate that apigenin interacts with the progesterone receptor (PR), albeit with lower affinity than endogenous progesterone [77]. In vivo, apigenin inhibits estrogenic effects and upregulates PR‐target genes [74].

Preclinical evidence shows that apigenin directly inhibits endometriotic cell growth and promotes apoptosis. Apigenin decreases proliferation, induces G0/G1 arrest, and triggers apoptosis in human endometriosis cell lines (VK2/E6E7, End1/E6E7). This occurs via increased intracellular ROS and activation of the unfolded protein response [72]. Apigenin mitigated LPS‐induced endometritis in mouse models of uterine inflammation. It attenuated histopathologic damage, reduced MPO activity, decreased MDA levels, and suppressed TNF‐α and IL‐1β production. This demonstrates broader anti‐inflammatory potential within the reproductive tract [81]. Figure 2 illustrates these early‐stage laboratory findings of apigenin, its cellular pathways, and current hurdles in clinical translation for endometriosis. Apigenin is a phytochemical for endometriosis that targets multiple pathogenic pathways, including NF‐κB, VEGF/VEGFR2, PI3K/AKT, HIF‐1α, and estrogen receptors, thereby reducing lesion proliferation, angiogenesis, and pain [48, 82]. However, clinical data specific to apigenin in endometriosis remain unavailable. No randomized controlled trials or patient‐level outcomes were identified. Preclinical studies demonstrate a mechanism for apigenin use. Rigorous clinical investigations are essential to establish safety, optimal dosing, and therapeutic efficacy in women with endometriosis. Regarding translational readiness, apigenin is under preclinical investigation. Studies utilizing rat models of endometriosis demonstrate in vivo efficacy. Human clinical trials for this indication are not yet available.

FIGURE 2.

Preclinical evaluation of Apigenin: Molecular mechanisms and translational research gaps in endometriosis. The schematic summarizes the current state of evidence on the therapeutic potential of Apigenin. Left Panel (in vitro Mechanisms): Apigenin inhibits proliferation in endometriotic stromal cells (VK2/E6E7, End1/E6E7), inducing cell cycle arrest and apoptosis [72]. It also exhibits anti‐inflammatory and phytoprogestin activities by regulating the levels of inflammatory markers like TNF‐alpha and interacting with Progesterone Receptors (PR) [77]. Right Panel (in vivo Models): In animal studies using Lipopolysaccharide (LPS)‐induced models, Apigenin treatment significantly attenuates inflammation in mammary tissues. This is characterized by downregulation of oxidative stress markers, including Myeloperoxidase (MPO), and reductions in pro‐inflammatory cytokines (TNF‐alpha, IL‐1beta) [83]. Lower Panel (Research Gaps): Preclinical data indicate multi‐targeted action (NF‐kappa B, VEGF, PI3K/AKT, and ER pathways). The schematic highlights a lack of validation in endometriosis animal models and human clinical data. ER, Estrogen Receptor; G0/G1, Gap 0/Gap 1 phases of the cell cycle; IL‐1beta, Interleukin‐1 beta; LPS, Lipopolysaccharide; MDA, Malondialdehyde; MPO, Myeloperoxidase; NF‐kappa B, Nuclear Factor kappa‐light‐chain‐enhancer of activated B cells; PI3K/AKT, Phosphoinositide 3‐kinase/Protein Kinase B; PR, Progesterone Receptor; TNF‐alpha, Tumor Necrosis Factor‐alpha; VEGF, Vascular Endothelial Growth Factor.

6.2. Puerarin

Puerarin, a phytoestrogen isoflavone derived from the roots of Pueraria species, has demonstrated significant therapeutic potential for the treatment of endometriosis [84]. Puerarin inhibits endometrial cell migration and adhesion. It downregulates invasion‐associated proteins (MMP‐2 and MMP‐9) and suppresses cell proliferation [57, 84]. In a rat model, oral administration of puerarin resulted in a significant reduction in the size of abnormal endometrial tissue. It lowered overall estrogenic levels, thus preventing the lesions from growing and developing. Puerarin suppresses estrogen‐stimulated ESC proliferation [85]. It reduces cyclin D1 and cdc25A expression and inhibits membrane‐initiated non‐genomic ERK signalling. It also acts by inhibiting aromatase P450 (P450arom), present at both the mRNA and protein levels, thereby further reducing local estrogen levels. It inhibits the invasion and vascularization in the abnormal endometrial tissues when tested on chicken membranes. This ability to prevent angiogenesis and invasion is associated with reduced build‐up of MMP‐9, ICAM‐1, and VEGF in cells and further increases the amount of the blocking agent TIMP‐1 [84]. It further suppresses the amounts of both estradiol (E2) and prostaglandin E2 (PGE2) by disrupting the self‐sustaining cycle of E2 production. Puerarin upregulates 17β‐hydroxysteroid dehydrogenase‐2 (17β‐hsd‐2) (E2 inactivation) and downregulates 17β‐hydroxysteroid dehydrogenase‐1 (17β‐hsd‐1) (E2 synthesis) [57].

Puerarin demonstrates therapeutic efficacy in endometriosis. It mediates anti‐inflammatory and anti‐angiogenic activities. This is evidenced by its suppression of VEGF and ICAM‐1 levels [84]. A 2012 study definitively demonstrated that puerarin attenuates the proliferation of endometriotic cells induced by 17β‐estradiol [85]. This anti‐proliferative mechanism involves the downregulation of key cell cycle regulators and pro‐inflammatory mediators: Cyclin D1, COX‐2, and CYP19 [85]. Furthermore, its benefits come from inhibiting the phosphorylation of the ERK pathway, a critical signalling cascade involved in cellular proliferation [85]. Puerarin binds to estrogen receptors, competing with endogenous estrogen [77]. It has an anti‐angiogenic property that suppresses endometriotic cells, which are usually driven by estrogen [84]. Puerarin blocks the aromatase enzyme (CYP19A1), critical for estrogen production in endometriotic tissues [57].

Preclinical studies using mouse models demonstrated that Pueraria flower extract inhibits endometriosis lesion formation and inflammatory activity [86]. Figure 3 illustrates puerarin's clinical potential and biological modes of action in endometriosis treatment. Pueraria (20 mg/kg) demonstrates substantial therapeutic value in a rat model of endometriosis and in the clinic [57]. PEE treatment attenuated 11Z and 12Z cell migration. This effect was consistently observed in wound‐healing and transwell assays [86]. Puerarin has been shown to exhibit various biological activities, including antioxidant, hepatoprotective, antidiuretic, neuroprotective, cardiovascular protective, nephroprotective, anti‐inflammatory, antipyretic, analgesic, muscle relaxant, antimutagenic and anticancer activities [87].

FIGURE 3.

Therapeutic efficacy and mechanistic pathways of Puerarin in endometriosis. The schematic illustrates the multidimensional impact of puerarin on endometriotic progression. Left Panel (Preclinical Validation): In vivo rat models show that oral puerarin suppresses lesion growth, lowers systemic estrogen levels, and inhibits inflammatory activity [57] without inducing renal toxicity [88]. Complementary in vitro studies demonstrate puerarin‐mediated modulation of cell proliferation [85]. Right Panel (Mechanistic Potential): Puerarin exerts therapeutic effects via mechanisms including downregulation of Prostaglandin E2 (PGE2) [57], reduction of estradiol levels [57], and inhibition of cellular invasion [84] and proliferation [85]. Clinical Status: This figure highlights a significant translational gap, noting that despite promising safety and efficacy data in animal models, clinical evidence regarding the efficacy of puerarin in human patients with endometriosis remains limited [89]. PGE2, Prostaglandin E2.

6.3. Xanthohumol

Xanthohumol (XN), a prenylated flavonoid in Humulus lupulus L. (hops), demonstrates potential for endometriosis treatment [90]. XN inhibits cellular proliferation, suppresses inflammation, and induces anti‐angiogenic effects in lesions [58]. XN selectively reduces lesion microvascular density, sparing healthy uterine and ovarian vasculature. This anti‐angiogenic effect proceeds via inhibition of specific intracellular signalling pathways. XN also attenuates inflammation by inhibiting pro‐inflammatory mediators, including MCP‐1 and TNF‐α [91]. XN modulates inflammatory mediators, including IL‐1, NF‐κB, and Akt [77]. In murine models of endometriosis, oral XN administration suppressed lesion growth; it inhibited neovascularisation and cellular proliferation. Crucially, XN spared the normal structure, proliferation, and perfusion of healthy uterine and ovarian tissue, suggesting a safe profile for endometriosis therapy [58]. XN exhibits anti‐cancer activity across multiple lineages: respiratory (non‐small cell lung cancer), haematological (leukaemia), digestive (hepatocellular carcinoma, pancreatic, colon), and genitourinary (breast, prostate, ovarian) [92].

We assessed xanthohumol efficacy in 10–14‐week‐old female BALB/c mice (18–20 g) under standard housing conditions [58]. We determined the estrous stage via vaginal lavage and microscopic examination. All procedures complied with international animal care guidelines [58]. The bioactivity of xanthohumol includes anti‐obesity, hypoglycaemic, anti‐hyperlipidaemic, anti‐cancer, anti‐angiogenic, and anti‐inflammatory activities [93]. In anti‐inflammatory activity, nitric oxide (NO) plays a crucial role in many types of inflammatory responses and is also involved in carcinogenesis as described in Figure 4. XN also shows reduced levels of inflammatory mediators, such as monocyte chemoattractant protein‐1 and tumour necrosis factor‐alpha (TNF‐α), in LPS‐stimulated RAW 264.7 mouse macrophages and U937 human monocytes [91]. These data demonstrate XN efficacy in both in vivo and in vitro models [94]. Xanthohumol inhibits various proliferation activities and activates nuclear factor‐κB in pancreatic cancer cells, suppresses VEGF and IL‐8 mRNA expression, and also suppresses tumour growth and angiogenesis in a subcutaneous xenograft model [95]. Xanthohumol's translational status is Stage 2, supported by consistent animal‐model evidence with no clinical data [93].

FIGURE 4.

Preclinical efficacy and safety profile of Xanthohumol in endometriosis management. The schematic outlines the therapeutic impact of Xanthohumol in in vivo and in vitro models. Top Left (In Vivo Mouse Model): Administration of Xanthohumol in mouse models resulted in reduced vascularization through anti‐angiogenic mechanisms and inhibition of tumor growth [96]. Importantly, the treatment exhibited a favourable safety profile in preclinical models [92]. Bottom & Center (Mechanistic Actions): Preclinical studies in immune cells and in vitro cultures highlight multiple mechanisms of action, including inhibition of cell proliferation, suppression of angiogenesis, and reduction of inflammatory mediators [97]. The compound also modulates oxidative stress and involves Nitric Oxide (NO) production pathways [97]. Top Right (Clinical Perspective): While current preclinical data position Xanthohumol as a highly promising therapeutic candidate, there is a specific need for clinical studies to validate these findings in human subjects. NO, Nitric Oxide.

6.4. Black Garlic

Garlic possesses established medicinal properties, used extensively as a spice and therapeutic agent [98]. Research evaluates its pharmacological mechanisms. Black garlic comprises fermented garlic, produced at temperatures between 60°C and 90°C [99].

Black garlic exhibits antioxidant, anti‐inflammatory, and anticancer activities. These properties facilitate endometriosis treatment. These activities also enhance immune system function, combating infections and bacterial pathogens [100]. Black garlic, a fermented product, contains reduced allicin content, which enhances absorption [101]. Compared with fresh garlic, black garlic contains antioxidant compounds, including polyphenols, flavonoids, pyruvate, and Maillard reaction intermediates [102]. Black garlic treatment of endometriotic stromal cells suppresses TNF‐α‐induced intercellular adhesion molecule (ICAM‐1) and vascular adhesion molecule (VCAM‐1) expression. This suppression occurs via nuclear factor‐kappa B (NF‐κB) inhibition [18]. Beyond antioxidant and anti‐inflammatory properties, black garlic exhibits hepatoprotective, nephroprotective, anti‐allergic, and immunomodulatory activities. Oxidation processes in living organisms generate free radicals, including ROS. The body's defence system neutralises these species by blocking oxidation. This mechanism prevents the accumulation of non‐neutralized free radicals, which induce oxidative stress, inflammation, and carcinogenesis.

Compounds in black garlic that significantly reduce inflammation include S‐Allyl‐Cysteine (SAC) and 5‐hydroxymethylfurfural (5‐HMF) [102, 103]. S‐Allyl‐Cysteine (SAC) from black garlic induces an anti‐inflammatory response. HaCaT keratinocyte studies demonstrate SAC suppresses pro‐inflammatory cytokine production, specifically TNF‐α and IL‐1β [104]. SAC also inhibits TNF‐α‐induced activation of p38 and JNK MAP kinases [104]. Preclinical mouse model studies demonstrated decreased activation of inflammatory mediators: Nitric Oxide (NO), tumour necrosis factor (TNF‐α), and interleukin 6 (IL‐6). This reduction was achieved by blocking iNOS, COX‐2, and NF‐κB [105]. We evaluated 18 women (aged 25–45) with advanced endometriosis during laparoscopic intervention for dysmenorrhea and pelvic pain. Black garlic shows chemopreventive effects in vitro and in vivo across various cancer types [106]. The hexane extract of black garlic induces caspase‐dependent apoptosis via both the intrinsic and extrinsic pathways in leukaemia cells [107] as shown in Figure 5: A translational study on how black garlic and SAC affect inflammatory pathways in endometriosis. Among the agents reviewed, black garlic has translational evidence in vitro and in vivo [101]. Current clinical evidence for black garlic in endometriosis‐related dysmenorrhea remains limited. Small sample size, lack of randomisation, and absence of controls preclude definitive therapeutic conclusions.

FIGURE 5.

Translational evaluation of black garlic and S‐AllylCysteine (SAC) in endometriosis and inflammation. The schematic contrasts preclinical mechanistic findings with preliminary clinical observations. Left Panel (Preclinical Studies): In vitro studies in endometrial stromal cells and HaCaT keratinocytes show that black garlic and its bioactive component, SAC, exert potent anti‐inflammatory effects by inhibiting the nuclear factor kappa B (NF‐kappaB) pathway. This inhibition suppresses pro‐inflammatory cytokines (TNF‐alpha, IL‐1beta) and downregulates adhesion molecules (ICAM‐1 and VCAM‐1). In vivo mouse models corroborate these findings, showing reductions in inflammatory mediators (iNOS, COX‐2, IL‐6, NO) and macrophage activity. Additionally, hexane extracts of black garlic exhibit anti‐proliferative activity in leukemia cell lines. Right Panel (Clinical Studies): In a clinical cohort of 18 women (ages 25–45) diagnosed with advanced endometriosis, treatment protocols for dysmenorrhea and pelvic pain were evaluated, often involving laparoscopic intervention. COX‐2, Cyclooxygenase‐2; HaCaT, Human immortalized keratinocytes; ICAM‐1, Intercellular Adhesion Molecule 1; IL‐1beta, Interleukin‐1 beta; IL‐6, Interleukin‐6; iNOS, Inducible Nitric Oxide Synthase; NF‐kappaB, Nuclear Factor kappa‐light‐chain‐enhancer of activated B cells; NO, Nitric Oxide; SAC, S‐AllylCysteine; TNF‐alpha, Tumor Necrosis Factor‐alpha; VCAM‐1, Vascular Cell Adhesion Molecule 1.

6.5. Pine Bark (Pycnogenol)

Pycnogenol, a complex procyanidin and polyphenol mixture, is harvested from French maritime pine bark [108]. Pine bark extract, combined with oral contraceptives, demonstrably reduces endometriosis‐related chronic pelvic pain [109]. Pycnogenol administration significantly facilitated pain reduction [109]. This agent exhibits anti‐inflammatory and antithrombotic effects [110]. These effects strongly support its critical role in endometriosis management. Pycnogenol inhibits both Cyclooxygenase‐1 (COX‐1) and COX‐2 enzymatic activity. It further suppresses Nuclear Factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB)‐dependent gene expression, consequently inhibiting the inflammatory cascade [109, 110]. Multiple studies have investigated Pycnogenol, the registered trademark for French maritime pine bark extract [60].

Pycnogenol definitively relieves pain, reduces CA‐125 markers, and enhances patient quality of life in endometriosis. Importantly, it does so without disrupting normal hormonal balance or menstrual cycles [60]. The product operates via decreased cell viability, caspase‐independent pathway induction, and increased plasma antioxidant capacity. Pycnogenol blocks inflammatory response‐related post‐translational events [109]. Clinical trials included 58 surgically diagnosed women. These patients underwent conservative endometriosis operations [60]. Treatment with Pycnogenol (60 mg/kg for 48 weeks) elicited a gradual symptom decrease. Conversely, Gonadotropin‐releasing hormone agonists (Gn‐RHa) demonstrated faster initial efficacy, but resulted in symptom recurrence by 24 weeks. Pycnogenol administration did not impact estrogen levels or menstrual cycles, unlike Gn‐RHa which lowered CA‐125. This outcome clearly establishes Pycnogenol as a superior therapeutic alternative to Gn‐RHa for endometriosis treatment [60].

A Japanese multicentre trial demonstrates Pycnogenol efficacy as a Gn‐RHa alternative for endometriosis symptom management (Figure 6). Pycnogenol provides analgesic and antispasmodic effects on menstrual cramps and premenstrual syndrome [60]. Classified at Stage 4 (clinically usable candidate), Pycnogenol demonstrates symptom control and CA‐125 reduction in a 48‐week RCT without hormonal disruption [82].

FIGURE 6.

Preclinical mechanisms and clinical efficacy of Pine Bark Extract (Pycnogenol) in the management of endometriosis. The schematic details Pycnogenol pharmacology and clinical trial evidence. Left Panel (Preclinical & Mechanistic Studies): Pycnogenol exhibits significant anti‐inflammatory, anti‐thrombotic, anti‐proliferative, and pro‐apoptotic properties [109]. These mechanisms collectively suppress the development and maintenance of endometriotic lesions. Right Panel (Clinical Studies): Data from a multicentre clinical trial conducted across four hospitals in Japan, involving 58 surgically diagnosed women, demonstrate the clinical utility of Pycnogenol [60]. Patients experienced faster initial symptom relief (within 24 weeks), with significantly reduced menstrual pain, cramps, and abdominal pain. Furthermore, treatment with Pycnogenol (administered as Pycnonon) lowered serum CA‐125 levels without affecting estrogen levels or menstrual cycles. The schematic positions Pycnogenol as a viable therapeutic alternative to Gonadotropin‐Releasing Hormone agonists (Gn‐RHa) for symptom management. CA‐125, Cancer Antigen 125; Gn‐RHa, Gonadotropin‐Releasing Hormone agonist.

6.6. Milk Thistle (Silymarin)

Silymarin, a compound extracted from Asteraceae, historically supported lactation [111]. It is a flavonolignan mixture isolated from S. marianum that demonstrates antioxidant, anti‐inflammatory, pro‐apoptotic, and anti‐proliferative effects [112]. It also exhibits free radical scavenging and anti‐fibrotic activity. Due to its anti‐inflammatory activity, it inhibits neutrophil migration to the site of inflammation. It modulates inflammatory processes involving NF‐κB, Kupffer cells, and eicosanoids (prostaglandins and leukotrienes) to regulate gene expression. It also inhibits IL‐6, miR‐155 expression, TNF‐α, interferon‐γ, IL2, and Inducible Nitric Oxide Synthase (iNOS) [113].

Some studies suggest that silymarin, with its active ingredient silibinin, has immunomodulatory properties and is a beneficial agent in the treatment of endometriosis and other autoimmune diseases. It contains silybin, which has been shown to have hepatoprotective effects, support the immune system, and, further, help treat endometriosis by modulating oestrogen metabolism [113, 114, 115]. Silymarin is effective in reducing the size and histopathology grade of endometrial lesions [62].

A 2018 study (n = 12) evaluated SMN (50 mg/kg orally) in induced endometriosis. After 28 days, SMN decreased lesion size (p < 0.05) and reduced tissue mRNA levels of GDNF, gfra1, Bcl‐6b, and Bcl‐2 compared to controls. The SMN + endometriosis group showed a significant enhancement in ERK1/2 expression (p < 0.05), reduced vascularization area, and increased indices [61, 116]. Silymarin provides antioxidant defence through direct free radical scavenging, inhibition of free radical formation, and maintenance of redox status [117, 118].

These medicinal herbs exhibit therapeutic efficacy for liver complications, dyspepsia, uterine haemorrhage, and menstrual disorders [119, 120]. We demonstrate that silymarin (silibinin) exhibits antiproliferative and apoptotic effects on human endometriotic cell lines VK2/E6E7 and End1/E6E7. In retrograde menstruation mouse models, silibinin decreases endometriotic lesion burden by inhibiting inflammatory cytokines [121]. Silymarin administration reduces endometrial lesions and increases serum total antioxidant activity in animal models [122]. Silymarin occupies Stage 2 of translational development, supported by preclinical evidence and one small randomised controlled trial (RCT) [122]. Large‐scale clinical trials for broader endometriosis indications remain necessary (Figure 7).

FIGURE 7.

Preclinical evaluation and therapeutic potential of Silymarin in endometriosis. In vitro (Top Left): Silymarin treatment downregulates proliferation and upregulates apoptosis in VK2 and End1 cell lines, indicating inhibitory effects on endometriotic cell survival. In vivo (Bottom): Silymarin reduces vascularisation and lesion size in Sprague‐Dawley rat models via anti‐angiogenic activity. Retrograde menstruation mouse models (Right) demonstrate reduced endometriotic lesions via inflammatory cytokine blockade. Clinical Status (Top Right): Dedicated clinical trials for endometriosis are pending, though established therapeutic applications include uterine haemorrhage and menstrual disorders. End1, Endocervical cell line; VK2, Vaginal keratinocyte cell line.

6.7. Green Tea (Epigallocatechin‐3‐Gallate: EGCG)

Green tea contains bioactive compounds such as polyphenols, amino acids, vitamins, chlorophylls, and caffeine. It contains significant types of catechins, including EGCG, epigallocatechin, epicatechin‐3‐gallate, and epicatechin [50]. EGCG's anti‐angiogenic effects suppress endometriosis by blocking VEGF‐C/VEGFR2 signalling. This inhibits fibrosis, migration, and invasion via MAPK/Smad pathways, inducing endometriotic lesion regression in preclinical models [47, 50, 65, 123, 124].

Preclinical studies have demonstrated that green tea inhibits HeLa cell growth and reduced lung and liver metastasis in BALB/c mice with 4T1 tumours [125, 126]. These studies consistently report that EGCG exerts beneficial effects on endometriotic lesions, mediated by its antioxidant, anti‐inflammatory, and anti‐metastatic properties. Most studies consistently report EGCG's anti‐proliferative effects. Treatment with EGCG induces significant regression of endometriotic lesions, as evidenced by substantial reductions in size, volume, weight, and number, and a corresponding impairment in cellular proliferation [127].

While preclinical studies have demonstrated that epigallocatechin gallate (EGCG) exerts a beneficial effect on endometriosis, a significant research gap remains in translating these findings into clinical practice [50]. No clinical studies have examined EGCG's therapeutic effects in humans with endometriosis (Figure 8). Consequently, well‐designed clinical trials are warranted to validate the efficacy and safety of green tea and to elucidate its full therapeutic potential in patients with endometriosis [50]. EGCG remains at Stage 2 of translational development; while preclinical data consistently demonstrate anti‐proliferative, anti‐angiogenic, and anti‐fibrotic effects in rodent endometriosis models, no clinical trials have yet investigated its therapeutic role in human endometriosis.

FIGURE 8.

Current status of Epigallocatechin Gallate (EGCG) research in lesion regression. The schematic illustrates EGCG's therapeutic potential in preclinical settings. Human clinical validation is currently absent. Left panel (Preclinical Studies): Evidence from in vitro cell lines and in vivo animal models demonstrates EGCG action via multiple molecular pathways. These include apoptosis induction (programmed cell death), anti‐proliferative activity, and anti‐fibrotic effects [128]. Furthermore, EGCG exhibits potent anti‐angiogenic properties by downregulating Vascular Endothelial Growth Factor C (VEGF‐C) and its receptor VEGFR2, resulting in significantly decreased vascularization and subsequent regression of lesions [128]. Right panel (Clinical Studies): Despite robust preclinical data, specific clinical trials are notably absent, highlighting a critical research gap. This lack of human validation underscores the need for translational studies to confirm the efficacy and safety of EGCG in clinical populations [50]. EGCG, Epigallocatechin Gallate; VEGF‐C, Vascular Endothelial Growth Factor C; VEGFR2, Vascular Endothelial Growth Factor Receptor 2.

7. Clinical Application and Limitations

Herbal treatments demonstrate efficacy as complementary or alternative endometriosis management strategies. These agents possess multifaceted pharmacological properties: anti‐inflammatory, anti‐angiogenic, anti‐proliferative, and antioxidant effects [129]. Clinical studies, specifically evaluating apigenin, black garlic, puerarin, green tea catechins, and other CHM phytochemicals, confirm improvements in endometriosis pain symptoms, menstrual regularity, and ovarian function [54, 77]. Additionally, herbal therapies are generally associated with lower systemic side effects compared to conventional hormonal or surgical treatments, offering an attractive option for patients seeking long‐term or adjunctive management [54, 77].

7.1. Regulatory Classification of Reviewed Natural Products

Reviews of natural products must differentiate pharmaceutical drug candidates, standardized herbal medicines, and dietary or health supplements. These categories differ in regulatory requirements, quality control standards, dose standardization, safety assessment requirements, and legal/scientific efficacy claims [130]. Lack of differentiation among these classes confuses clinicians. This impedes assessment of agent suitability for prescription, complementary supplementation, or pre‐clinical drug development investment.

Pharmaceutical candidates require active compound isolation and regulatory submission (NDA or IND). Efficacy must be demonstrated in randomised controlled trials (RCTs) [131]. Standardised herbal medicines contain validated bioactive markers. Manufacturers adhere to Good Manufacturing Practice (GMP) under national regulatory frameworks (EMA, AYUSH, PMDA, CFDA) [132]. Dietary supplements are food‐derived wellness products. These lack requirements for disease‐specific efficacy, rigorous dose standardisation, or safety surveillance [133].

Pycnogenol (pine bark extract) approximates a standardised phytomedicine. It demonstrates pharmaceutical potential through defined procyanidin content and positive endometriosis RCT data [134]. Silymarin utilises existing EMA herbal monographs. This regulatory framework permits adaptation for gynaecological use, pending further clinical evidence. Apigenin and EGCG remain dietary supplements. Compelling pharmacology is offset by limited clinical trial data and unresolved bioavailability profiles. Black garlic occupies an intermediate position. Standardised S‐Allyl‐Cysteine (SAC) content permits phytopharmaceutical classification, though clinical evidence remains limited to observational studies [135]. Puerarin and xanthohumol require human PK, dose‐finding, and safety profiles for investigational candidacy. Systematic animal model data support this potential [90, 136]. These distinctions are clinically significant. Clinicians must differentiate between prescribing dietary supplements, standardised herbal medicines, and investigational pharmaceuticals.

Significant limitations restrict the clinical application of herbal therapies in endometriosis. Preclinical studies, variable formulations, and heterogeneous trials generate inconsistent efficacy data [137]. High product variability in purity and bioactive content complicates safety profiles. Potential herb–drug interactions with conventional therapies remain poorly characterised [77]. We prioritise large‐scale, randomised controlled trials and rigorous phytopharmaceutical standardisation for mainstream clinical integration [138] (Table 2).

TABLE 2.

Regulatory category and translational pathway for natural products in endometriosis.

Compound	Proposed category	Rationale	Regulatory pathway / Quality considerations
Apigenin	Dietary supplement/nutraceutical	Dietary flavonoid source; preclinical models demonstrate significant anti‐inflammatory effects [75]	FSSAI/FDA dietary supplement pathway; quality control of flavonoid content needed; bioavailability formulation work required [139]
Puerarin	Standardised herbal medicine/phytopharmaceutical candidate	Isolated isoflavone; preclinical models demonstrate significant reduction of E2 and PGE2 markers [77]	Puerarin TCM regulatory framework (China); phytomedicine monograph development required; standardized dosing in rat models (20 mg/kg) [140]
Xanthohumol	Standardised herbal medicine/investigational phytopharmaceutical	Prenylated flavonoid derived from Humulus lupulus; controlled animal studies demonstrate anti‐angiogenic activity [128]	Investigational new drug (IND) pathway consideration; requires dose standardisation and safety profiling in humans [66]
Black Garlic (SAC)	Standardised herbal medicine/health supplement	Garlic supplementation; clinical data in 60 patients [59]	Dual regulatory pathway. Requires further RCT validation. Standardise SAC content [17]
Pine Bark (Pycnogenol)	Pharmaceutical‐grade standardised herbal medicine	Therapeutic alternative in the treatment of endometriosis [60]	Phytomedicine regulatory pathway (EMA, Japanese PMDA); clinical dossier largely available; suitable for prescription consideration as adjunctive therapy [141]
Milk Thistle (Silymarin)	Standardized herbal medicine/nutraceutical	Well‐characterized extract (silybin content); established hepatoprotective use; emerging evidence for endometriosis from animal studies and one endometrioma RCT [61]	EMA herbal monograph exists for liver use; endometriosis indication would require additional RCTs; standardisation of silybin percentage needed [142]
Green Tea (EGCG)	Dietary supplement/nutraceutical	Dietary source. Preclinical studies confirm efficacy. Prodrug formulation (Pro‐EGCG) overcomes bioavailability limitations [50]	Dietary supplement pathway. Advanced formulations (nanocarriers, Pro‐EGCG) necessitate investigational drug pathway assessment; monitor liver safety at high doses [142]

Abbreviations: AYUSH, Ministry of Ayurveda, Yoga & Naturopathy, Unani, Siddha, and Homeopathy; CFDA, China Food and Drug Administration; EGCG, Epigallocatechin‐3‐gallate; EMA, European Medicines Agency; GMP, Good Manufacturing Practice; IND, Investigational New Drug; OCP, Oral Contraceptive Pill; PMDA, Pharmaceuticals and Medical Devices Agency (Japan); SAC, S‐Allyl‐Cysteine; TCM, Traditional Chinese Medicine.

7.2. Positioning of Natural Products in Endometriosis Management

Reviews of phytomedicines lack defined clinical pathway integration [17]. We categorize five endometriosis clinical indications: (1) pain control, (2) postoperative recurrence prevention, (3) fertility‐preserving management, (4) hormonal therapy combination, and (5) long‐term supportive care. Each context demands distinct evidence, patient populations, outcome measures, and risk‐benefit considerations. Table 3 presents a structured clinical positioning matrix.

TABLE 3.

Clinical positioning matrix of natural products in endometriosis management.

Compound	Pain control	Recurrence suppression	Fertility‐preserving management	Hormonal adjunct efficacy	Long‐term supportive care
Apigenin	—	—	◑ (phytoprogestin, fertility‐sparing potential) [77]	—	◑ (antioxidant adjunct)
Puerarin	◑ (anti‐inflammatory) [85]	◑ (preclinical lesion reduction) [57]	◑ (anti‐estrogenic, aromatase inhibition) [84]	—	—
Xanthohumol	◑ (anti‐inflammatory, preclinical) [128]	◑ (preclinical: inhibits regrowth) [58]	—	—	—
Black Garlic (SAC)	◑ (clinical: dysmenorrhea relief) [59]	—	—	—	✓ (low‐risk supplement, immunomodulatory)
Pine Bark (Pycnogenol)	✓ (clinical RCT evidence) [60]	✓ (clinical: comparable to GnRHa) [60]	✓ (no hormonal disruption, fertility‐sparing) [77]	✓ (adjunct to OCP in RCT) [77]	✓ (48‐week clinical data) [77]
Milk Thistle (Silymarin)	◑ (demonstrates anti‐inflammatory effect) [77]	—	—	—	◑ (hepatoprotective; adjunct use) [77]
Green Tea (EGCG)	◑ (anti‐inflammatory, preclinical) [50]	—	◑ (anti‐angiogenic, estrogen‐neutral) [63]	—	◑ (antioxidant adjunct) [143]

Legend: ✓ = Clinical evidence available; ◑ = Preclinical or mechanistic evidence supporting this role (clinical data absent);—= No current evidence or not applicable.

Abbreviations: CA‐125, Cancer Antigen 125; EGCG, Epigallocatechin‐3‐gallate; GnRHa, gonadotropin‐releasing hormone agonist; OCP, oral contraceptive pill; PR, progesterone receptor; SAC, S‐allyl‐cysteine.

7.2.1. Pain Control

The major disabling symptoms of endometriosis are chronic pelvic pain and dysmenorrhea [11]. These represent a major unmet need in women who are unable to tolerate or do not have an adequate response to conventional analgesics or hormonal agents [144]. Of the agents reviewed, Pycnogenol provides the strongest clinical evidence for this indication. Clinical studies demonstrate that Pycnogenol significantly reduces pain and functions as a therapeutic alternative to GnRHa in women with endometriosis [60]. Apigenin and puerarin have shown anti‐inflammatory effects in preclinical endometriosis models through mechanisms including the modulation of COX‐2 and TNF‐α [77, 145]. Clinical pain data are lacking for these agents, and their position in pain management remains investigational at this time.

7.2.2. Postoperative Recurrence Prevention

Recurrence of endometriosis occurs in 30%–50% of patients within five years after surgery, demonstrating the clinical need for safe, long‐term agents to prevent re‐implantation and lesion regrowth [39]. Short‐term hormonal suppression (GnRHa, COCs, progestins) remains the primary postoperative strategy, but it is not recommended for women wishing to conceive [146]. Pycnogenol demonstrates efficacy in this setting: A Japanese RCT showed its use as an alternative to GnRHa post‐surgically [60]. Anti‐angiogenic agents, including xanthohumol and puerarin, suppress lesion vascularization in preclinical models [58, 84]. Clinical trials are required to validate these candidates for postoperative recurrence prevention.

7.2.3. Fertility‐Preserving Management

Endometriosis‐related infertility affects 25%–50% of infertile women [147]. Fertility preservation remains a clinical priority. Conventional hormonal therapy suppresses ovulation and precludes fertility efforts [32]. Natural products modulate inflammatory and proliferative pathways without ovarian suppression. This establishes a clinical niche. Pycnogenol improves endometriosis‐associated pain without altering oestrogen levels or menstrual cycles [134]. It serves as a non‐hormonal adjunct for conception. Apigenin potentially restores endometrial receptivity via phytoprogestin activity: progesterone receptor interaction and Hand2 transcription upregulation [74]. Clinical evaluation in infertile women is absent. EGCG supports fertility‐treatment cycles via oestrogen‐neutral, anti‐angiogenic mechanisms. Bioavailability limitations and insufficient clinical safety data preclude definitive recommendations [50]. Future fertility‐focused trials in endometriosis‐associated infertility with natural products should include endometrial receptivity biomarkers, ovarian reserve parameters and live birth rates as co‐primary outcomes [10].

7.2.4. Combination With Hormonal Therapy

As hormonal therapies are the mainstay of endometriosis treatment, the important clinical question remains whether natural products can be safely and beneficially administered as adjuncts [10]. In one study, Pycnogenol combined with an oral contraceptive pill (OCP) demonstrated a greater reduction in chronic pelvic pain compared to OCP monotherapy [109]. This mechanism is biologically plausible. Pycnogenol inhibits NF‐κB [109] via non‐oestrogenic mechanisms [134]. Apigenin warrants caution; as a phytoprogestin, it competes with PR [74, 148]. Combination with synthetic progestins remains unstudied [74]. The safety of combining these agents with hormonal therapy is poorly characterised; co‐administration necessitates clinical trial validation.

7.2.5. Long‐Term Supportive Care

Endometriosis necessitates lifelong management post‐reproductive age [149]. Long‐term supportive care reduces symptom burden, preserves quality of life, and mitigates the cumulative adverse effects of prolonged pharmaceutical exposure [66, 150]. In this regard, dietary supplements with an established safety profile are particularly appealing. Standardised black garlic as a health supplement has been found to provide immunomodulatory and antioxidant effects [99]. Silymarin provides hepatoprotective support for patients receiving long‐term hepatotoxic pharmacological regimens (e.g., danazol) [151]. Pycnogenol has clinical evidence for supportive use, showing sustained symptom control without endocrine disruption [134]. EGCG requires clinical vigilance; high‐dose green tea extract supplementation correlates with liver injury (hepatotoxicity) [152]. This emphasises the importance of dose standardisation and monitoring even for naturally derived substances.

8. Future Direction

Future research prioritizes rigorous clinical validation, standardization, and mechanistic elucidation of phytochemical effects. Preclinical studies demonstrate that compounds including apigenin, EGCG, and various Chinese herbal formulations modulate inflammatory pathways, angiogenesis, and oxidative stress. Large‐scale, randomized controlled trials remain limited [47, 153]. Standardizing herbal preparations with defined bioactive components and optimized dosing regimens will be essential to ensure reproducibility, safety, and clinical efficacy [139, 154].

Modern drug delivery systems, including nanocarriers or phytochemical‐loaded gels, enhance bioavailability and targeted therapeutic action to improve patient outcomes [155]. Molecular biology, omics technologies, and systems pharmacology accelerate the identification of novel herbal candidates and their precise mechanisms of action in endometriosis [156]. Personalized herbal therapy, guided by genetic, epigenetic, and microbiome profiling, may enable more effective, tailored interventions in the future [156, 157]. Furthermore, long‐term safety studies, evaluation of herb–drug interactions, and comparative effectiveness research against conventional therapies are crucial to integrating herbal approaches into mainstream endometriosis management [153]. Overall, future directions emphasize evidence‐based, standardized, and personalized herbal interventions that complement conventional strategies while addressing current knowledge gaps.

Advances in personalized medicine, integrative care, and mechanistic research drive the development of endometriosis herbal treatments [142]. Strategies combine herbal therapies with anti‐inflammatory diets (omega‐3 fatty acids, antioxidants) to optimize therapeutic outcomes [158]. These dietary patterns reduce systemic inflammation and circulating estrogen concentrations, alleviating endometriosis symptoms [159, 160]. Additionally, the development of multi‐herbal regimens that target specific symptoms such as pelvic pain, heavy menstrual bleeding, and fatigue offers a more tailored approach.

Garlic extract has shown efficacy in reducing pelvic pain and cramping associated with endometriosis [59]; compounds (apigenin, xanthohumol) exert anti‐inflammatory and anti‐angiogenic effects [52]. Integration of artificial intelligence (AI) and digital health technologies drives next‐generation herbal research [161]. AI‐driven models accelerate phytochemical identification, optimize formulations, and predict treatment efficacy [161]. Machine learning integration with clinical data enables patient‐specific treatment strategies [161]. Additionally, digital tools like mobile apps can support real‐time symptom monitoring [162]. These advancements increase precision, data integration, and patient‐centricity in clinical practice.

9. Conclusion

Endometriosis constitutes a complex, multifactorial gynaecological disorder, necessitating challenging long‐term management [163, 164]. Conventional treatments, such as hormonal therapy and surgery, offer temporary relief [165]. However, they are limited by high recurrence rates [165]. Natural plant‐derived agents, such as Epigallocatechin‐3‐Gallate (EGCG) and curcumin, demonstrate promising adjunctive therapeutic potential. These agents operate via anti‐inflammatory, antioxidative, and anti‐angiogenic pathways to inhibit lesion growth [66]. Proapoptotic actions facilitate ectopic endometrial tissue clearance [166]. Despite this, clinical use is limited by poor bioavailability and lack of standardisation [17, 50]. Concerns also include variable evidence and possible herb–drug interactions [166]. Future management requires integration of these botanicals with conventional treatments through personalized approaches. This necessitates rigorous randomised controlled trials, improved delivery systems, and strict quality control to ensure safety, efficacy, and reproducibility.

Funding

This review paper, hence funding is not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Data Availability Statement

Data sharing is not applicable; we generated no datasets during this study.