Pueraria mirifica: a critical review of the ethnobotany, phytochemistry, pharmacology and challenges in standardization and safety

Abstract

Background:

Pueraria candollei var. mirifica (Airy Shaw and Suvat.) Niyomdham (Pueraria mirifica), locally known as “White Kwao Krua” or “white kudzu”, is a renowned medicinal botanical drug indigenous to Southeast Asia, particularly Thailand and Myanmar. It has long been utilized in ethnomedicine for estrogen-related conditions and age-associated functional decline. This review critically evaluates the nexus between its botanical characteristics, traditional ethnopharmacological uses, and contemporary evidence regarding its therapeutic potential.

Materials and Methods:

A structured literature search was conducted across multiple international and Chinese databases up to 2025, with screening based on predefined inclusion and exclusion criteria focusing on botanical identity, chemical composition, pharmacological activity, toxicological evidence, and clinical findings. Taxonomic validity and geographic distribution were verified using Plants of the World Online (POWO) and the Global Biodiversity Information Facility (GBIF). The names and chemical formulas of secondary metabolites were verified using the PubChem database, and the structures were drawn using ChemDraw 22.2.

Results:

Phytochemical studies on the rhizomes of P. mirifica showed that it contains 106 kinds of secondary metabolites, including benzopyrans, isoflavones and their glycosides, coumarins, steroids, fatty acids and their derivatives, and other metabolites. Pharmacological evidence demonstrates that P. mirifica exhibits potent estrogenic, anti-osteoporotic, and antioxidant activities, alongside neuroprotective and immunomodulatory effects. Clinical data suggest that its high concentration of potent phytoestrogens effectively mitigates vasomotor symptoms and urogenital syndromes in menopausal women, while positively influencing lipid metabolism and bone mineral density.

Conclusion:

P. mirifica represents a high-potency phytoestrogenic candidate for menopause management. Nevertheless, the translation from traditional use to clinical standardization is hindered by a lack of rigorous pharmacokinetic data and inconsistent quality control of metabolites. Future research should move beyond descriptive summaries toward mechanistic studies that define long-term safety margins and standardized dose–response relationships in order to ensure therapeutic reliability.

1 Introduction

Since the 20th century, global attention toward perimenopausal symptoms and their long-term complications has intensified. Hormone Replacement Therapy (HRT) remains the gold standard for clinical intervention (Kandale et al., 2025); however, its long-term application is frequently constrained by concerns regarding elevated risks of breast cancer and cardiovascular events (Vigneswaran and Hamoda, 2022; Intharuksa et al., 2025). Consequently, there is an urgent global demand for safe, plant-derived alternatives. Pueraria candollei var. mirifica (Airy Shaw and Suvat.) Niyomdham (Pueraria mirifica), commonly known as “White Kwao Krua”, has emerged as a premier candidate due to its unique profile of potent phytoestrogens, notably the chromene derivatives miroestrol and deoxymiroestrol (Chansakaow et al., 2000).

Pueraria candollei var. mirifica (Airy Shaw and Suvat.) Niyomdham (P. mirifica), commonly known as White Kwao Krua or white kudzu, is a perennial climbing plant. Historically, P. mirifica has been used for more than a century, primarily as a rejuvenating tonic to alleviate age-related ailments in menopausal women (Maruyama et al., 2014). It is essential to distinguish P. mirifica from its congener, Pueraria montana var. lobata. While the latter is widely used in East Asia for cardiovascular disorders and febrile diseases, it lacks the specific benzopyranoid scaffold that grants P. mirifica its exceptional estrogenic potency (Malaivijitnond, 2012). Despite its burgeoning commercial presence in the global nutraceutical and cosmetic markets, the scientific evidence supporting P. mirifica remains fragmented. Current literature often provides descriptive summaries that lack a rigorous, critical assessment of study quality, molecular mechanisms, and the translational strength of clinical data.

This review aims to provide a critical and systematic synthesis of P. mirifica, bridging its ethnopharmacological heritage with contemporary scientific evidence. Rather than offering a purely descriptive compilation, this review evaluates the strength, limitations, and translational relevance of the available evidence across ethnobotanical, phytochemical, pharmacological, toxicological, and clinical domains. Particular emphasis is placed on distinguishing comprehensive chemical reporting from pharmacologically prioritized constituents, separating mechanistic plausibility from experimentally supported effects, and differentiating preclinical findings from clinically actionable evidence. In addition, this review identifies key sources of inconsistency, including phytochemical variability, formulation heterogeneity, limited pharmacokinetic characterization, and insufficient long-term clinical validation, all of which currently constrain the development of P. mirifica as a standardized evidence-based botanical drug. To provide an integrated overview, the major bioactive metabolites of P. mirifica, their proposed estrogen receptor-related mechanisms, and the reported pharmacological effects are summarized in Figure 1.

FIGURE 1

2 Review methodology

To ensure transparency and reproducibility, a structured approach was employed for literature identification, screening, and evaluation. A database search was conducted across ScienceDirect, Google Scholar, PubMed, Springer, CNKI, and Wanfang using combinations of the following search terms: (“Pueraria mirifica” OR “White Kwao Krua” OR “Kwao Krua”) AND (phytochemistry OR chemical metabolite OR metabolite OR pharmacology OR biological activity OR clinical trial OR menopause). The search initially identified 2,976 records potentially relevant to the topic. After duplicate removal and screening according to the predefined inclusion and exclusion criteria, 202 reports were finally included in this review. The retrieved literature was further categorized into ethnobotanical, phytochemical, pharmacological, toxicological, and clinical domains. Evidence interpretation was informed not only by topic relevance but also by study type and methodological detail, with explicit consideration of whether findings were derived from in vitro experiments, animal studies, or human investigations. Particular attention was given to study design clarity, sample size, dosage information, control settings, formulation characterization, and the extent to which reported findings supported mechanistic interpretation or clinical translation. The taxonomic validity of P. mirifica was verified using authoritative taxonomic sources, and its botanical distribution was cross-checked against reliable biodiversity databases. In addition, the chemical nomenclature and molecular structures of the identified compounds were verified using the PubChem database and ChemDraw (version 22.2). Accordingly, this article should be understood as a structured and critical evidence synthesis rather than a formal systematic review with meta-analysis. The overall literature retrieval, screening, and study selection workflow is summarized in Figure 2.

FIGURE 2

3 Botanical profile and traditional use

3.1 Taxonomy and vernacular names

Accurate taxonomic identification is essential for distinguishing P. mirifica from closely related taxa and for ensuring consistency across ethnobotanical, phytochemical, and pharmacological studies. According to Plants of the World Online (POWO), P. mirifica belongs to the family Fabaceae and the genus Pueraria. In addition to its formal taxonomic placement, the species is known by different vernacular names across Southeast Asia, reflecting regional linguistic variation and its long-standing traditional use. Reported local names of P. mirifica across Southeast Asia are summarized in Table 1.

3.2 Geographic distribution

The currently available evidence indicates that P. mirifica is centered in mainland Southeast Asia, with Thailand representing the principal area of confirmed native occurrence. The species was originally described from Thailand, and subsequent studies have reported its broad distribution in Thai deciduous forests, particularly in the northern, western, and northeastern regions, with additional collections from multiple provinces across the country (Kashemsanta et al., 1952; Malaivijitnond, 2012; Cherdshewasart et al., 2008). By contrast, records from neighboring countries remain less well supported. Occurrence in Myanmar has been reported in the literature, but it has not been confirmed to the same taxonomic or floristic standard as records from Thailand (Malaivijitnond, 2012). Reports referring to Laos and Vietnam are also available in secondary literature or local studies, but these should be interpreted cautiously because the supporting evidence is weaker than that for Thailand (Rani et al., 2022a; Vui et al., 2019). Accordingly, Thailand is treated here as the confirmed occurrence area, whereas Myanmar, Laos, and Vietnam are shown as reported occurrences with lower evidential confidence. The geographic distribution and evidence levels of P. mirifica in mainland Southeast Asia are summarized in Figure 3.

FIGURE 3

3.3 Gross morphology

Morphological characterization provides an important basis for species recognition and helps support the botanical authenticity of materials used in phytochemical and pharmacological investigations. Pueraria mirifica is a woody climber that can reach up to 12 m in length and is characterized by a twining habit, slender branched stems, trifoliate leaves, and prominent tuberous roots. The stems are glabrous, ribbed, and become flaking with age. The leaves are pinnately trifoliate, with acuminate apices, broadly ovate to obtuse bases, entire margins, and a pubescent surface. The underground organs are globose to ovoid tuberous roots, typically 5–40 cm in diameter, with a pale yellow, glabrous outer surface and white internal tissue that becomes progressively lignified with age. The gross morphological characteristics of P. mirifica, including its climbing habit, trifoliate leaves, and tuberous roots, are shown in Figure 4.

FIGURE 4

3.4 Ethnopharmacological relevance and traditional knowledge

3.4.1 Botanical origin and taxonomic evolution of Pueraria mirifica

Historical records from Myanmar indicate that P. mirifica was traditionally distinguished from related P. mirifica materials on the basis of vegetative morphology and root coloration. These records specifically emphasized the medicinal importance of P. mirifica as the therapeutically valued form. This text specifically detailed the morphological distinctions between P. mirifica and Butea superba, highlighting the medicinal value of the former as a therapeutic agent or health supplement.

The taxonomic history of P. mirifica has undergone several revisions, reflecting earlier uncertainty in species identification and later clarification based on morphological and botanical evidence. After initial confusion with related taxa, the species was ultimately recognized as Pueraria mirifica and later reclassified as Pueraria candollei var. mirifica to distinguish it from closely related forms within the genus. This taxonomic clarification is not merely historical; it has direct relevance to phytochemical authentication, quality control, and the interpretation of pharmacological studies, because inconsistent nomenclature in the literature may obscure the true botanical identity of the materials investigated.

3.4.2 Traditional applications and ethnopharmacological context

In ethnobotanical practice, harvested P. mirifica undergo a rigorous preparation process, including removal of impurities, thorough washing, peeling of the periderm, and a secondary rinse. The cleaned roots are then sliced thinly, dried (either via solar or oven drying), and pulverized into a fine powder. Alternatively, the powder is mixed with honey to form boluses (pills) for precise dosing and improved formulation stability.

According to the P. mirifica Prescription, P. mirifica can be administered as a monotherapy or in polyherbal formulations with milk, honey, or other traditional Thai botanical drugs. Its traditional therapeutic indications include: rejuvenation, improved sleep, enhanced physical strength, promoting appetite, breast enlargement, preventing hair loss or graying, and memory enhancement.

Historical texts specify a dosage range of 30–500 mg/day, recommending a gradual escalation from low to high doses. These traditional applications provide an important ethnopharmacological rationale for subsequent scientific investigation, particularly in relation to women’s health, menopausal symptom management, and age-associated functional decline (Maruyama et al., 2014). However, the translational pathway from traditional use to modern application remains incomplete. Specifically, traditional indications do not directly identify the active constituents responsible for these effects, nor do they resolve questions regarding dose standardization, tissue selectivity, long-term safety, or formulation consistency. For this reason, the following sections examine how phytochemical evidence, mechanistic pharmacology, and clinical findings collectively support—yet also limit—the modern therapeutic interpretation of P. mirifica.

3.4.3 Comparative botanical analysis and identification

Based on traditional classifications, P. mirifica is frequently discussed alongside two other regionally significant botanicals: B. superba and Mucuna collettii. While all three species are utilized in Southeast Asia for kidney tonification and share superficial morphological similarities, their botanical origins, chemical profiles, and therapeutic applications differ significantly. Notably, P. mirifica is primarily indicated for female health due to its unique phytoestrogen content; in contrast, the latter two species are traditionally administered for male vitality. Phytochemical investigations have further delineated these distinctions, revealing that B. superba lacks the potent chromene miroestrol, which is diagnostic for P. mirifica, though it possesses higher concentrations of the isoflavones daidzein and genistein (Manosroi and Manosroi, 2005). Such chemical divergence highlights the risks of substitution, especially as identification becomes increasingly challenging when these materials are marketed in powdered or processed forms. To address the limitations of traditional organoleptic identification and ensure consumer safety, molecular diagnostic techniques—including polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) (Wiriyakarun et al., 2013) and Amplification Refractory Mutation System (ARMS) (Intharuksa et al., 2020)—have been rigorously implemented to resolve inter-species ambiguities.

Within the Pueraria genus, P. candollei and its variety var. mirifica are highly susceptible to adulteration due to their nearly identical vegetative morphology. Early literature suggested that differentiation was only possible during the flowering period (March-April) by observing inflorescence density and pod pubescence (Yusakul et al., 2011). However, subsequent research has revealed fundamental differences at both the chemical and genetic levels: (1) Phytohormonal Profile: var. mirifica contains the unique marker mirificin and significantly higher concentrations of puerarin, with metabolic pathways that are highly sensitive to environmental induction (Korsangruang et al., 2010; Boonsnongcheep et al., 2010). (2) Molecular Markers: While standard PCR-RFLP may lack the resolution for this specific variety (Wiriyakarun et al., 2013), recent studies identify a single nucleotide polymorphism (G/C variation) at position 702 of the matK gene and stipule length (>0.9 cm vs. <0.4 mm) as definitive diagnostic markers (Charoensup et al., 2024). Integrating morphological, biochemical, and molecular approaches is essential to ensure clinical efficacy and safety. Furthermore, a literature review reveals that some studies still erroneously use the umbrella term P. candollei when the subject is actually P. candollei var. mirifica. We emphasize the urgent need for standardized identification and unified nomenclature to ensure the scientific rigor of future research.

3.5 Quantitative variation in chemical constituents: influence of genetics, geography, and seasonality

Traditional knowledge underscores the critical importance of harvest timing and processing methods to ensure the therapeutic efficacy of P. mirifica. Recent quantitative studies have validated these claims, revealing that the chemical profile of P. mirifica is a dynamic result of complex interactions between genetic background (cultivars), geographic origin, seasonal fluctuations, and extraction technologies. This variability directly influences the amounts of key phytoestrogens (e.g., miroestrol, deoxymiroestrol), which are often used as markers for product potency and activity, making standardized quality control essential in commercial production. Without rigorous authentication and quantification of these bioactive constituents, products derived from different sources can vary widely in their chemical profile, leading to inconsistent pharmacological effects (Rani et al., 2022). Quality assessment frameworks for herbal products emphasize the need to evaluate authentication, compound quantification, safety, and efficacy before formulation.

3.5.1 Geographic and genetic chemovariation

Quantitative analysis demonstrates substantial inter-provincial and intra-provincial variation in phytoestrogen content across Thailand. Total isoflavone levels can vary by over 10-fold between regions, with the highest concentrations reported in Kanchanaburi province (198.29 mg/100 g) and significantly lower levels in Nan province (18.61 mg/100 g) (Cherdshewasart et al., 2007). Even within a single province such as Chiang Mai, a 3-fold variation exists between districts (e.g., 240.09 mg/100 g in Doi Tao vs. 76.52 mg/100 g in Chaiprakarn), confirming a clinal pattern of chemical distribution (Suwanvijitr et al., 2010).

Beyond geographic factors, distinct cultivars (e.g., P. mirifica -I to P. mirifica -V) exhibit divergent “chemovarieties” even when cultivated under identical environmental conditions; for instance, P. mirifica -I consistently demonstrates superior estrogenic activity and isoflavonoid accumulation (up to 1007.47 ± 72.22 mg/100 g) compared to P. mirifica -II (Cherdshewasart and Sriwatcharakul, 2007).

Recent multi-omic integrative studies further elucidate these phenotypic discrepancies, revealing that concatenated chloroplast DNA barcodes (including matK, rpoC1, trnH-psbA, and rps16) provide superior resolution for discriminating P. mirifica cultivars compared to nuclear internal transcribed spacer (ITS) markers. This genetic divergence is closely coupled with differential gene expression; specifically, high-performing cultivars (such as “NA”) exhibit a coordinated upregulation of key biosynthetic genes—including IFS, CYP81E63, and the novel UGT2—within the tubers, directly correlating with elevated daidzein and puerarin levels. Such findings underscore that precise cultivar selection, guided by integrated barcoding and transcriptomic profiling, is indispensable for ensuring the quality, safety, and standardized therapeutic efficacy of P. mirifica products (Huynh et al., 2024).

3.5.2 Seasonal dynamics and metabolic flux

The accumulation of bioactive metabolites is highly sensitive to seasonal changes, driven by the differential expression of synthetic enzymes such as UDP-glycosyltransferase (UGT) and CHI (Jungsukcharoen et al., 2016). (1) Summer (April): Generally, represents the optimal harvest window. Total isoflavones can be 15 to 37 times higher than in the rainy season. Puerarin, for instance, peaks at 228.41 ± 87.80 mg/kg in summer compared to only 14.48 ± 6.03 mg/kg in the rainy season (Cherdshewasart and Sriwatcharakul, 2007). When P. mirifica grew, the growth rate increased with the increase of temperature from 16 °C to 27 °C (Major et al., 1975). (2) Rainy season (October): Characterized by a shift toward aglycones, with daidzein reaching its relative peak, though total isoflavone activity is lowest due to high water content and metabolic dilution (Cherdshewasart et al., 2008). (3) Winter (February): Genistein content typically peaks during this period, and biological activity remains relatively high, comparable to summer (Cherdshewasart et al., 2008).

3.5.3 Impact of extraction and processing methods

The recovery of these constituents is further dictated by the extraction methodology. Traditional ethanol extraction (80%) yields a crude recovery of approximately 5.38%, whereas sequential partitioning into dichloromethane (DCM) concentrates highly active lipophilic metabolites like miroestrol and deoxymiroestrol, despite a lower mass yield of 0.22% (Sookvanichsilp et al., 2008). Modern intensification techniques have significantly outperformed these traditional protocols; for instance, ultra-fine pulverization (100–300 mesh) combined with ultrasonic-microwave synergistic extraction (UMSE) achieves a flavonoid extraction rate of 4.86% in just 30 min (Zhu et al., 2023). Building upon these advancements, the field is shifting towards sustainable pharmacognosy through the use of Natural Deep Eutectic Solvents (NADES) and advanced analytical integration. Recent studies demonstrate that honey-based NADES (H-NADES) not only serves as an eco-friendly solvent for the high-sensitivity extraction and icELISA-based quantification of daidzin, but also facilitates the in situ bioconversion of daidzin into the more bioactive aglycone daidzein via endogenous β-glucosidase activity (Yusakul et al., 2021). Furthermore, the integration of green extraction technologies—such as enzyme-assisted and supercritical fluid extraction—with high-resolution UPLC-MS/MS and NMR platforms has been pivotal in elucidating the complex biosynthetic pathways and broad pharmacological spectrum of puerarin, encompassing its cardiovascular, neuroprotective, and osteogenic effects (Liga and Paul, 2024).

3.5.4 Conclusion on material standardization

These findings highlight that material standardization is a central translational challenge in P. mirifica research rather than a merely technical issue. A practical quality framework should include at least five elements: authenticated botanical identity, control of raw material origin and harvest conditions, chemical fingerprinting with prioritized marker compounds, batch-to-batch consistency testing, and bioactivity-linked quality evaluation. In this context, variables such as plant age, cultivar selection, season of harvest, and post-harvest processing are not minor background factors but major determinants of metabolite composition and therefore of pharmacological consistency. Consequently, future standardization efforts should move beyond reliance on single-marker quantification and instead adopt integrated metabolic fingerprinting strategies combined with safety evaluation and pharmacokinetic characterization to support clinically reliable product development.

Importantly, this phytochemical variability is not only a compositional issue but also a translational one. Variations in cultivar, geographic origin, seasonality, and processing conditions can directly alter the relative abundance of active metabolites, thereby affecting pharmacological consistency, batch-to-batch reproducibility, comparability across studies, and ultimately the clinical reliability of P. mirifica-derived products. This is one of the key reasons why promising preclinical findings cannot yet be assumed to translate into uniform therapeutic outcomes in human use.

4 Phytochemical composition

Pueraria mirifica possesses a complex and distinctive phytochemical profile. Although it shares several common isoflavonoids with other Pueraria species, such as Pueraria lobata, it is distinguished by the presence of benzopyranoid constituents, particularly deoxymiroestrol and miroestrol, which are widely regarded as characteristic phytoestrogenic compounds of this species. To date, more than 100 metabolites have been identified from P. mirifica, reflecting substantial chemical diversity. However, not all reported constituents appear to contribute equally to its pharmacological profile. Based on current evidence, chromenes—especially deoxymiroestrol and miroestrol—together with selected isoflavonoids and related compounds such as puerarin, daidzein, genistein, and kwakhurin, are currently the most biologically relevant constituents for interpreting the reported estrogenic and downstream pharmacological effects of P. mirifica. Accordingly, Table 2 and Figures 5, 6 should be interpreted not only as a comprehensive phytochemical inventory, but also as a basis for pharmacological prioritization and future standardization.

FIGURE 5

FIGURE 6

From a translational perspective, these chemically identified constituents should be interpreted in a graded manner, because only a subset currently has sufficient biological evidence to support mechanistic or therapeutic prioritization. Recent advances in high-throughput and multi-omics technologies have provided deeper insights into the chemical composition and biosynthesis of isoflavonoids and related metabolites in Pueraria species. For instance, integrated metabolomic and transcriptomic analyses have elucidated how key metabolites such as puerarin and daidzin accumulate at different developmental stages and correlate with the expression of UDP-glycosyltransferase and other biosynthetic genes, providing a comprehensive view of the regulatory networks governing secondary metabolite production (Hu et al., 2023).

Additionally, metabolome profiling combined with co-expression network analysis has been used to identify gene modules associated with flavonoid accumulation in distinct plant organs, leveraging PCA and WGCNA approaches to map regulatory landscapes (Zhu et al., 2024). These omics approaches exemplify the application of modern analytical methods such as liquid chromatography–tandem mass spectrometry (LC-MS/MS), PCA, and RNA sequencing (RNA-seq) to dissect the molecular mechanisms of bioactive compound synthesis and accumulation, thereby enriching phytochemical and pharmacological research on Pueraria. A separate integrated transcriptomic and targeted metabolomics study has further extended omics analysis to endogenous hormone dynamics during tuberous root expansion, illustrating the broader utility of high-throughput technologies in functional plant research (Wang et al., 2024).

4.1 Benzopyranoids

Among the benzopyranoids identified in P. mirifica, miroestrol and deoxymiroestrol are the most potent and diagnostic metabolites (Chansakaow et al., 2000a). Modern phytochemical evidence clarifies that deoxymiroestrol is the native constituent, whereas miroestrol is an oxidative artifact formed during post-harvest processing; crucially, deoxymiroestrol exhibits estrogenic potency an order of magnitude higher than its oxidized counterpart (Chansakaow et al., 2000). From a biosynthetic perspective, it is proposed that miroestrol originates from daidzein through a multi-step enzymatic sequence involving CYP81E-catalyzed hydroxylation, isoflavone reductase (IFR)-mediated reduction, and prenyltransferase (PT)-dependent prenylation. This pathway is substantiated by the significant co-expression of these candidate genes with daidzein accumulation and the corresponding phytochemical profiles of the species (Suntichaikamolkul et al., 2019).

However, the inherent chemical instability of these compounds poses a substantial challenge for product standardization, as improper storage can drastically diminish therapeutic efficacy (Udomsin et al., 2015). To address these limitations, research has bifurcated into two primary directions: Biotechnological Production: Optimized callus and cell suspension cultures have been developed, where the use of fructose as a carbon source can enhance deoxymiroestrol accumulation by up to 15.8-fold compared to wild roots (Udomsuk et al., 2011). Furthermore, complex synthetic routes, such as microwave-assisted siloxy-Cope rearrangement, have been established to provide high-purity crystalline standards for pharmacological validation (Ito et al., 2009; Shimokawa et al., 2013). Field-deployable Analysis: The field is shifting from laboratory-bound LC-MS/MS (Lee et al., 2017) toward high-throughput, point-of-need tools. Advanced immunochromatographic assays (ICA), immunochromatographic strips (ICS) (Krittanai et al., 2018), Fragment antigen-binding (Fab) fragments (Juengsanguanpornsuk et al., 2023), and ELISA techniques (Yusakul et al., 2018; Pongkitwitoon et al., 2019) are now employed to ensure supply chain integrity and verify metabolite concentrations (Chaingam et al., 2019; Sae-Foo et al., 2021; Masada et al., 2021; Chuphol et al., 2023).

4.2 Isoflavonoids and glycosides

Isoflavonoids are the most abundant phytoestrogens in P. mirifica, including daidzein, genistein, puerarin, and the species-specific marker kwakhurin. The species-specific marker kwakhurin is essential for authenticating the plant and distinguishing it from adulterants. Due to its extremely low natural abundance (0.0008%–0.007% w/w), developing robust synthesis and detection systems is crucial for quality control (Iwasaki et al., 2004; Chanpokapaiboon et al., 2018; Yusakul et al., 2019; Thanonkeo et al., 2024). Chemical synthesis of kwakhurin has evolved from early triisopropyl-protected routes to a total synthesis using MEM-protection (12% yield) (Ito et al., 2005), and recently to a highly efficient 3-step pathway (57% yield) validated by qNMR (Tsuji et al., 2020). For rapid standardization, immunodiagnostic methods offer significant advantages (Sakamoto et al., 2020; Phaisan et al., 2021; Sakamoto et al., 2022). A critical pharmacological consideration is that these metabolites predominantly exist as glycosides (e.g., daidzin). Their bioactivity depends on hydrolysis into aglycones by gut microbiota, a process subject to significant inter-individual variability (Makkliang et al., 2021). Recent omics findings (transcriptomic and proteomic) have elucidated the biosynthetic pathways, identifying key enzymes such as CHS, IFS, and UGT (Suntichaikamolkul et al., 2023). The expression of these enzymes is heavily influenced by the plant’s age and environmental factors, providing a scientific basis for the traditional emphasis on specific harvesting sites and maturity.

4.3 Coumestans

The coumestan profile, including coumestrol and unique mirificoumestans, further enriches the plant’s chemical diversity (Ingham et al., 1988). While their estrogenic activity is secondary to benzopyranoids, coumestrol exhibits multi-target effects, including anti-inflammatory and antioxidant activities. However, most current research remains at the stage of isolation and identification; direct pharmacological evaluation of these specific fractions from P. mirifica remains a priority for future studies.

4.4 Steroids, volatile oils, and fatty acids

Beyond the primary phytoestrogens, P. mirifica contains a complex matrix of secondary metabolites, including phytosterols (e.g., β-sitosterol, α-spinasterol), polysaccharides (Li et al., 2024), triterpenoids (squalene), and a diverse volatile profile comprising aldehydes, ketones, and terpenoids (e.g., germacrene D). Although these constituents are not considered diagnostic markers, metabolites like α-spinasterol exhibit documented cytotoxic and estrogen-like activities, potentially contributing to a synergistic “entourage effect” that modulates the plant’s overall therapeutic index (Jeon et al., 2005). Furthermore, the volatile oil fraction, while currently underutilized as cosmetic additives, presents an overlooked area for pharmacological research. From a quality control perspective, characterizing this “chemical background” is essential for ensuring batch-to-batch consistency and identifying interactions that may influence the bioavailability of major isoflavonoids. Future studies should transition from mere identification to physiological evaluation of these minor metabolites to support the rigorous standardization of P. mirifica-based functional products.

5 Pharmacological effects

The pharmacological literature on P. mirifica is extensive but uneven in evidentiary strength. The strongest body of support currently derives from phytochemical characterization, cell-based mechanistic studies, and animal experiments, whereas direct clinical validation remains comparatively limited. Accordingly, the biological effects discussed below should not be interpreted as equally established. In several areas, mechanistic plausibility is supported primarily by in vitro findings; in others, efficacy has been demonstrated in animal models but has not yet been confirmed in well-designed human studies (Jones et al., 1961; Ashby et al., 1999; Tiyasatkulkovit et al., 2012; Dickerson and Gore, 2007). Therefore, a critical distinction must be maintained between preclinical promise and clinically actionable evidence when evaluating the therapeutic potential of P. mirifica. The reported pharmacological effects of P. mirifica, together with their proposed mechanistic pathways and biological targets, are summarized in Table 3 and further illustrated in Figure 7. The pharmacological studies summarized in Table 3 include estrogenic, anti-osteoporotic, antioxidant, neuroprotective, vascular, reproductive, and anticancer-related evidence reported in previous in vitro and in vivo models (Bunmanop et al., 2011; Cherdshewasart and Sriwatcharakul, 2008a; Cherdshewasart and Sutjit, 2008c; Cherdshewasart et al., 2007; Geller and Studee, 2006; Hajirahimkhan et al., 2013; Islam et al., 2020; Jearapong et al., 2014; Jungsukcharoen et al., 2014; Kitisripanya et al., 2017a; Kongkaew et al., 2018; Lee et al., 2002; Liangdeng et al., 2024; Masrudin and Mohamad, 2015; Rattanapisit et al., 2021; Saetae, 2024; Singh, 2025; Trisomboon et al., 2006; Udomsuk et al., 2007; Udomsuk et al., 2011b; Xu et al., 2017; Yusakul et al., 2013).

FIGURE 7

5.1 Estrogenic activities and mechanisms

Pueraria mirifica has a distinctive estrogenic profile among botanical phytoestrogens. Soy (Glycine max) and red clover (Trifolium pratense) are also important sources of phytoestrogens, but their compositions differ: soy mainly contains genistein and daidzein, whereas red clover is richer in biochanin A and formononetin in addition to these isoflavones (Mikulić et al., 2024; Messina et al., 2025). Current evidence indicates that these isoflavones bind both ERα and ERβ, often with a preference for ERβ, and are therefore better described as SERM-like, tissue-dependent ligands rather than simply weak ER agonists (Messina et al., 2025; Intharuksa et al., 2025; Viscardi et al., 2025). In contrast, P. mirifica also contains highly estrogenic chromenes, particularly miroestrol and deoxymiroestrol, which contribute to its notable estrogenic activity and warrant careful dose selection and safety evaluation (Juengsanguanpornsuk et al., 2021a). Accordingly, its pharmacological effects should be interpreted in a tissue-specific and dose-dependent manner. Endometrial stimulation and reproductive endocrine effects remain important considerations in estrogen-sensitive tissues, but the safety of phytoestrogens cannot be generalized because it depends on the botanical source, chemical composition, formulation, route of administration, and duration of use. Thus, the appropriate dose or concentration of P. mirifica should be selected according to the intended therapeutic purpose, particularly in older women undergoing menopausal management. Detailed clinical dosage considerations are discussed separately in the clinical applications section below (Viscardi et al., 2025).

In the reproductive system, P. mirifica metabolites directly stimulate target tissues such as the uterus and vagina, inducing epithelial keratinization and increasing uterine weight in a manner analogous to 17β-estradiol (E₂) (Siangcham et al., 2010; Jaroenporn et al., 2014). However, this activity is characterized by a dual regulatory nature: while short-term or low-dose application can alleviate postmenopausal vaginal atrophy, chronic high-dose administration carries the risk of stimulating endometrial hyperplasia and potential oncogenesis (Cherdshewasart, 2003; Cherdshewasart et al., 2008a).

Beyond direct peripheral effects, P. mirifica modulates the hypothalamic–pituitary–gonadal (HPG) axis through negative feedback. By acting on the central nervous system, active metabolites inhibit the secretion of gonadotropin-releasing hormone (GnRH), subsequently suppressing the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) (Saenphet et al., 2005; Loutchanwoot et al., 2016; Loutchanwoot and Vortherms, 2018). This mechanism is evidenced by the inhibition of compensatory gonadotropin rises in ovariectomized animal models and the disruption of ovulation or induction of amenorrhea in non-human primates (Cherdshewasart et al., 2004; Trisomboon et al., 2004).

At the cellular level, P. mirifica exhibits a complex biphasic biphasic dose-dependent pattern. For instance, in MCF-7 breast cancer cell lines, low concentrations (approximately 1 µg/mL) promote proliferation via the classical ERα pathway, whereas high concentrations (100–1000 µg/mL) shift toward anti-proliferative or cytotoxic effects (Chivapat et al., 2000; Juengsanguanpornsuk et al., 2021). The clinical efficacy is further dictated by biotransformation: most constituents exist as glycosides that require hydrolysis by intestinal microbiota into active aglycones (e.g., daidzein to equol) for effective absorption (Dickerson and Gore, 2007; Yusakul et al., 2016). Furthermore, individual differences in hepatic cytochrome P450 (CYP) enzyme polymorphisms significantly influence the metabolic activation or inactivation of these metabolites, leading to divergent clinical responses (Trisomboon et al., 2007; Suntichaikamolkul et al., 2023).

5.2 Anti-osteoporotic activity

Osteoporosis is closely associated with the decline in sex hormone levels, particularly estrogen deficiency, which disrupts bone remodeling homeostasis and shifts bone turnover toward excessive resorption (Cheng et al., 2022; Walker and Shane, 2023). Current evidence further indicates that postmenopausal osteoporosis involves dysregulation of the OPG/RANKL axis, enhanced osteoclastogenesis, altered osteoimmune interactions, chronic low-grade inflammation, oxidative stress, and increased bone marrow adiposity (Fischer and Haffner-Luntzer, 2022; Iantomasi et al., 2023; Niu et al., 2024; Luo et al., 2025). Within this mechanistic framework, P. mirifica and its active metabolites have demonstrated considerable anti-osteoporotic potential across various experimental models through complex multi-target regulation (Wiriyaampaiwong et al., 2012). The major mechanisms underlying menopause-related osteoporosis and the potential intervention points of P. mirifica are summarized in Figure 8.

FIGURE 8

The anti-osteoporotic effects of P. mirifica have been extensively validated in animal models simulating postmenopausal or androgen-deficient states. In both ovariectomized (OVX) female rats and orchidectomized (ORX) male rats, oral administration of P. mirifica extract dose-dependently prevents declines in bone mineral density (BMD) and bone mineral content (BMC) while improving bone microstructure (Urasopon et al., 2007; Urasopon et al., 2008a; Kittivanichkul et al., 2016; Suthon et al., 2016; Saetae, 2024; Saetae et al., 2025), with significant protective effects typically observed at doses of 100 mg/kg/day and above (Chatuphonprasert et al., 2013). However, in OVX female rats, a high dose (e.g., 1000 mg/kg) still induced significant uterine weight gain, indicating that its estrogen-like stimulatory effect on the female reproductive system persists (Wang et al., 2013). These anti-bone-loss effects appear to arise from bidirectional regulation of both bone formation and bone resorption processes.

Consistent with these in vivo findings, in vitro studies have shown that P. mirifica extract and puerarin promote osteoblast proliferation and differentiation, accompanied by upregulation of osteogenic marker genes such as alkaline phosphatase (ALP) and type I collagen (Col I) (Tiyasatkulkovit et al., 2012; Udomsuk et al., 2012a; Tiyasatkulkovit et al., 2014; Wang et al., 2014). A key molecular basis for these effects involves modulation of the OPG/RANKL system, a pivotal signaling axis in bone metabolism. By activating estrogen receptors, these metabolites increase osteoprotegerin (OPG) expression while reducing receptor activator of nuclear factor kappa-B ligand (RANKL) expression, thereby elevating the OPG/RANKL ratio and suppressing osteoclastogenesis and osteoclast function (Anukulthanakorn et al., 2014). This regulatory process appears to depend on ERα and ERβ activation and involves downstream signaling pathways such as MEK/ERK and PI3K/Akt (Monthakantirat et al., 2014; Kulczyński et al., 2021).

Despite these promising findings, several limitations remain. Most preclinical studies have relied on crude extracts rather than standardized fractions, making it difficult to determine which specific metabolite, such as puerarin or miroestrol, contributes most to the bone-sparing effect. In addition, although the OPG/RANKL axis has been well characterized in vitro, the lack of long-term safety data in ORX/OVX models limits current understanding of potential chronic systemic risks. The clinical translation of P. mirifica also remains challenging because the oral bioavailability of its active metabolites is generally low, and interindividual responses may vary considerably depending on gut microbiota composition, genetic polymorphisms of hepatic metabolic enzymes, and baseline hormone status (Chatuphonprasert et al., 2016). Taken together, current evidence supports the anti-osteoporotic potential of P. mirifica, but further studies using standardized preparations, long-term safety evaluation, and clinically relevant pharmacokinetic strategies are still needed.

5.3 Neuroprotective effects and cognitive enhancement

Pueraria mirifica and its metabolites have demonstrated neuroprotective potential across various preclinical models, primarily mediated through estrogen receptor (ER) signaling, antioxidant defense, and anti-inflammatory pathways (Prasansuklab et al., 2020; Singh, 2025). The neuroprotective efficacy appears highly state-dependent, typically manifesting in estrogen-deficient environments.

Phytoestrogens from P. mirifica, such as miroestrol and deoxymiroestrol, can cross the blood-brain barrier to modulate ERα and ERβ signaling. Unlike synthetic estrogens, certain metabolites exhibit a higher binding affinity for ERβ, which is critical for hippocampal-dependent memory and avoidance of ERα-mediated peripheral proliferation (Malaivijitnond et al., 2004). Activation of these receptors triggers downstream cascades, including the PI3K/Akt and MAPK/ERK pathways, subsequently upregulating neurotrophic factors such as BDNF and CREB, and synaptic markers like synaptophysin (Chindewa et al., 2008; Monthakantirat et al., 2014; Li et al., 2017). For instance, in ovariectomized (OVX) models, miroestrol significantly ameliorated spatial memory deficits, while genistein reversed chemically-induced impairment (Kim et al., 2010). However, it must be noted that these studies often utilize pure metabolites at concentrations exceeding those achievable through standard dietary intake of botanical drugs, raising questions regarding the translational relevance of such dosages.

Pueraria mirifica further mitigates neurodegeneration by downregulating APP and BACE1 expression and inhibiting tau hyperphosphorylation (Anukulthanakorn et al., 2016). While the upregulation of endogenous enzymes (SOD, CAT) and inhibition of NF-κB mediated neuroinflammation are well-documented (Sucontphunt et al., 2011), most current evidence relies on phenotypic observations in animal models. A critical gap remains in understanding the direct molecular targets—whether these botanical metabolites act as direct enzyme modulators or indirect gene regulators. Furthermore, while the selective activation of ERβ suggests a favorable safety profile regarding reproductive tissues, long-term clinical data on its neuroprotective safety margin in humans are still absent.

5.4 Antioxidant and anti-inflammatory effects

Pueraria mirifica possesses both significant antioxidant and phytoestrogen-like activities. These two effects often act synergistically, forming the basis for its efficacy in alleviating menopausal symptoms, providing cardiovascular protection, and offering neuroprotection (Trisomboon et al., 2006).

Its antioxidant mechanism is multi-dimensional. Beyond direct ROS scavenging (Ratanachamnong et al., 2020; Rani et al., 2021), the core antioxidant capacity of P. mirifica metabolites (notably puerarin and miroestrol) stems from the modulation of the Nrf2/ARE signaling pathway. Rather than acting as mere chemical scavengers, these metabolites function as “para-hormetic” stressors or direct ligands that trigger the nuclear translocation of Nrf2, thereby initiating the transcription of Phase II detoxifying enzymes, including HO-1, NQO1, and SOD (Cai et al., 2024; Cao et al., 2024). However, it is critical to distinguish between these molecular regulatory effects and phenotypic outcomes; while increased SOD/CAT levels are widely reported (Udomsuk et al., 2012; Udomsuk et al., 2012b; Jearapong et al., 2014; Laddha and Kulkarni, 2021; Alkaç et al., 2022), the precise upstream triggers (e.g., whether via ER-dependent or ER-independent kinase activation) remain partially elucidated in botanical drug research.

The anti-inflammatory repertoire of P. mirifica is characterized by its specificity to different pathological models. In acute states, daidzein suppresses the TLR4/MyD88/NF-κB axis and inhibits MAPK/AKT phosphorylation, effectively limiting the “cytokine storm” (Yen et al., 2014; Feng et al., 2015). A novel dimension of its efficacy is the regulation of the “gut-liver-brain axis” by puerarin, which enhances the intestinal barrier and promotes production of short-chain fatty acids (SCFAs) (Sun et al., 2025). Critically, while many studies emphasize the inhibition of iNOS and pro-inflammatory cytokines (IL-1β, TNF-α) (Jantaratnotai et al., 2022), few have addressed the potential “pro-inflammatory” risks of P. mirifica at supra-physiological doses where estrogenic overstimulation might occur.

The convergence of these pathways is evident in estrogen-deficiency pathologies. Activation of ERβ by P. mirifica isoflavonoids often leads to the trans-repression of inflammatory genes (Jaroenporn et al., 2006; Atiq et al., 2019), suggesting that its anti-inflammatory benefits are inextricably linked to its receptor affinity (Zafar et al., 2023).

5.5 Complex effects on tumor cells: the phytoestrogen paradox

Pueraria mirifica and its active metabolites exhibit a complex “duality” in their effects on tumors, particularly hormone-sensitive ones. This biphasic effect is intrinsically linked to their structural similarity to 17β-estradiol and their dose-dependent affinity for estrogen receptors (ERα and ERβ) (Trisomboon et al., 2007). Under specific conditions, P. mirifica metabolites demonstrate significant anti-tumor potential. In various breast, ovarian, and colorectal cancer cell lines, these metabolites induce apoptosis by upregulating the Bax/Bcl-2 ratio and activating Caspase-3 (Yu and Li, 2006; Liu et al., 2017; Alizamir et al., 2025; Islam et al., 2025). Furthermore, they modulate carcinogen-metabolizing enzymes, specifically inhibiting the pro-carcinogenic CYP1B1 while upregulating protective phase II enzymes like NQO1 (Chatuphonprasert et al., 2016). Recent bioinformatics and molecular docking analyses suggested that P. mirifica may have anti-hepatocellular carcinoma (HCC) potential through targets including ADH1B and GHR (Li et al., 2025). Importantly, this prediction was not based solely on in silico evidence, as the same study further showed that the candidate compound hederagenin inhibited HepG2 cell viability and increased ADH1B protein expression, providing preliminary experimental support for ADH1B-related activity (Li et al., 2025). In addition, independent in vitro studies have shown that puerarin exerts anti-HCC effects by increasing chemosensitivity, inhibiting proliferation, and promoting apoptosis in liver cancer cells (Wu et al., 2017; Zhang et al., 2017). However, direct experimental validation of GHR as a functional target of P. mirifica in HCC remains limited and warrants further investigation.

A critical concern for clinical translation is the risk of tumor stimulation. Due to their potent estrogenic activity, P. mirifica extracts can act as ER agonists in low-estrogen environments or in ER-positive tumor contexts. In vitro studies have confirmed a classic “inverted U-shaped” dose-response curve: low concentrations of extract can promote MCF-7 cell proliferation, with inhibitory effects only occurring at significantly higher, possibly supra-physiological, doses (Cherdshewasart et al., 2007a).

The therapeutic window for the “anti-tumor” effect of P. mirifica is narrow and highly dependent on the host’s endogenous hormonal milieu and the specific metabolite profile (e.g., the ratio of miroestrol to deoxymiroestrol). The absence of standardized extract formulations in many reported studies (Jeon et al., 2005) complicates the comparison of results across different laboratories. For individuals with a history of hormone-dependent malignancies, the use of P. mirifica botanical drugs presents a non-negligible risk that warrants strict regulatory oversight and further longitudinal safety studies.

5.6 Effects on blood lipids and cardiovascular function

Pueraria mirifica and its active metabolites exhibit multifaceted regulatory effects on lipid metabolism and cardiovascular function. These actions are predominantly characterized as “estrogen-mimetic” cardioprotection, manifesting most effectively in hormone-deficient or hyperlipidemic environments (Cherdshewasart et al., 2008).

Preclinical evidence suggests that P. mirifica effectively lowers serum total cholesterol (TC) and LDL-C while improving the HDL-C/LDL-C ratio in high-cholesterol diet models (Charoenkul et al., 2005; Ratanachamnong et al., 2020). Mechanistically, this transition involves the activation of metabolic “sensing” pathways, including AMPK, PPARα, and FXR, which collectively coordinate hepatic lipid oxidation and cholesterol efflux (Ou et al., 2025). However, a critical assessment of the literature reveals significant heterogeneity in outcomes: while beneficial in pathological models, some studies report a transient elevation of triglycerides (TG) in subjects on a normal diet (Charoenkul et al., 2005). This discrepancy may stem from the non-selective activation of hepatic ERs, which can paradoxically stimulate VLDL synthesis, a nuanced risk often overlooked in purely descriptive reviews.

Pueraria mirifica enhances endothelium-dependent vasodilation, primarily by activating endothelial nitric oxide synthase (eNOS) and increasing nitric oxide (NO) bioavailability (Wattanapitayakul et al., 2005). It is important to note that most current findings rely on acute or sub-acute animal models. The efficacy of P. mirifica in preventing chronic cardiovascular events, such as myocardial infarction or stroke, remains unproven in large-scale clinical settings.

While its multi-target action offers a broader therapeutic window than isolated statins, its systemic estrogenic load remains a primary safety concern. The cardiovascular benefits must be meticulously weighed against the potential risks to hormone-sensitive tissues, necessitating further research into tissue-selective estrogen receptor modulators (SERMs) derived from P. mirifica.

5.7 Other pharmacological potentials

Pueraria mirifica exhibits diverse secondary pharmacological effects, ranging from systemic immunomodulation to tissue-specific protective roles.

Immunomodulatory and Prostatic Health: Crude polysaccharides from P. mirifica have shown non-specific immunostimulatory activity in vitro by promoting CD69 expression in T-lymphocytes (Burana-Osot et al., 2010). More specifically, in male reproductive health, aqueous extracts have demonstrated potential in attenuating testosterone-induced benign prostatic hyperplasia (BPH). This effect is mediated through the inhibition of 5α-reductase and the restoration of zinc ion homeostasis via zinc transporter upregulation (Masrudin and Mohamad, 2015; Mohamad et al., 2019). Critically, these findings suggest a potential role for P. mirifica in modulating male hormonal imbalances, though the interference with androgen signaling requires careful long-term safety monitoring.

Psychopharmacology and Dermal Applications: Recent studies (Tantipongpiradet et al., 2019; Tadsaichol et al., 2024) have highlighted antidepressant-like effects, where metabolites activate ERβ to upregulate BDNF and tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin synthesis. These findings position P. mirifica as a candidate for managing postmenopausal depressive symptoms. In dermatology, n-hexane extracts were found to stimulate melanin synthesis via tyrosinase activation (Manosroi et al., 2018), offering a scientific basis for traditional hair-darkening claims.

Genoprotective and Agricultural Applications: Beyond human health, P. mirifica ethanol extracts exhibit significant antimutagenic potential by protecting against chemical-induced genetic damage (Lapcharoen et al., 2005). Additionally, its insect growth-regulating activity against Aedes aegypti larvae suggests potential for bio-pesticide development (Cherdshewasart et al., 2009). However, the dual use of the plant in both therapeutic and pesticidal contexts necessitates a rigorous evaluation of systemic toxicity to ensure that bioactive metabolites do not pose risks of genotoxicity in human consumers.

5.8 Pharmacokinetics, metabolism, and individual variability

5.9 Toxicological profile and safety margin

The potent phytoestrogenic activity of P. mirifica is the foundation of its pharmacological effects, but it also constitutes its primary source of safety risk. Current research indicates that its toxicity is clearly dose-dependent and time-cumulative, suggesting that the safety margin for long-term use may be relatively narrow (Cherdshewasart, 2003).

Major toxic manifestations are concentrated in the reproductive, hematological, and potential carcinogenic systems. In female rodent models, high-dose exposure (≥100 mg/kg/day) results in significant endocrine-disrupting effects, including endometrial hyperplasia and hydrometra. Critically, in non-human primates, these dosages can induce irreversible amenorrhea, raising concerns about its long-term impact on the hypothalamic-pituitary-ovarian (HPO) axis (Chivapat et al., 2000; Trisomboon et al., 2005; Jaroenporn et al., 2007). In males, reproductive toxicity is manifested as reduced sperm motility and testicular atrophy (Jaroenporn et al., 2006). Beyond reproductive organs, hematopoietic toxicity—including bone marrow suppression and non-reversible hemolysis—has been observed in chronic toxicity studies, highlighting a systemic risk that persists even after cessation of treatment (Chivapat et al., 2000).

While the acute oral LD₅₀ remains low, the Lowest Observed Adverse Effect Level (LOAEL) is approximately 100 mg/kg/day in rats. The pharmacological dosages used in many efficacy studies (10–50 mg/kg) are in close proximity to this LOAEL, indicating a narrow safety window. The therapeutic doses often used in pharmacological studies (10–50 mg/kg) fall within a range that is dangerously close to the LOAEL, underscoring the fragility of the safety margin. Much of the existing safety data relies on rodent models, which may fail to accurately predict human risk due to interspecies variations in hepatic CYP450 isoforms and gut microbiota-mediated metabolism of deoxymiroestrol. Furthermore, the lack of standardized metabolic profiling in these studies complicates the differentiation between therapeutic efficacy and potential carcinogenicity, particularly concerning estrogen-sensitive mammary tumors (Kakehashi et al., 2016). In summary, while P. mirifica exhibits significant pharmacological benefits, the gap between therapeutic and toxic doses suggests that careful consideration of the safety margins is necessary. Further research involving large-scale human trials is crucial to better define these boundaries and ensure the safe use of the plant for therapeutic purposes.

6 Clinical applications

Clinical evidence suggests that P. mirifica may have therapeutic relevance for menopausal symptom management and genitourinary health, particularly in relation to vasomotor symptoms, vaginal atrophy, and selected quality-of-life outcomes. However, the translational strength of this evidence remains limited because most studies have involved relatively small sample sizes, short intervention periods, heterogeneous formulations, and incomplete standardization of dose and constituent composition. In addition, long-term safety assessment remains insufficient, particularly with regard to endometrial effects, endocrine regulation, and the use of P. mirifica in women with differing baseline hormonal status or comorbidities. For these reasons, the current human data should be interpreted cautiously, with attention to both the reported benefits and the important limitations that affect translational reliability. The published human clinical studies evaluating Pueraria mirifica formulations in menopausal symptom management and genitourinary health are summarized in Table 4.

6.1 Improvement of vasomotor symptoms and general menopausal symptoms

Clinical investigations have consistently highlighted the potential of P. mirifica in alleviating vasomotor symptoms (VMS), which are primarily attributed to its high-potency chromenes, such as deoxymiroestrol. This metabolite exhibits significantly higher estrogenic activity compared to common soy isoflavones by interacting more robustly with estrogen receptors (ERα and ERβ) to stabilize hypothalamic thermoregulation (Li Y. et al., 2025).

Early pilot studies utilized daily doses of 200 mg of raw root powder, reporting marked subjective improvements in the Modified Greene Climacteric Scale (MGCS) (Muangman and Cherdshewasart, 2001). However, these open-label designs are inherently susceptible to significant placebo effects, necessitating more rigorous validation. A subsequent Phase III randomized controlled trial (n = 60) compared a daily dose of 50 mg of P. mirifica against standard conjugated equine estrogen (CEE) therapy, finding no significant difference in efficacy for reducing MGCS scores over 24 weeks (Chandeying and Sangthawan, 2007). This suggests that P. mirifica might serve as a viable alternative for patients seeking non-hormonal options, although its dose-response relationship remains poorly defined. These studies generally reported a significant decline in symptom scores after 3–6 months of treatment (Lamlertkittikul and Chandeying, 2004; Chandeying and Lamlertkittikul, 2007). Further dose-comparison studies (n = 52) indicated that 25 mg and 50 mg doses were equivalently effective (Virojchaiwong et al., 2011), hinting at a potential “ceiling effect” in its therapeutic window.

Critically, while the initial efficacy is promising, the clinical evidence remains fragmented. Most trials suffer from small cohort sizes (n < 71), short follow-up durations (typically <6 months), and a lack of standardized phytochemical characterization of the extracts used. Without quantification of the highly unstable deoxymiroestrol in the trial medication, the reproducibility of these clinical outcomes across different batches remains questionable.

6.2 Improvement of genitourinary syndrome of menopause (GSM)

Topical administration of P. mirifica represents a specialized therapeutic modality for Genitourinary Syndrome of Menopause (GSM), specifically addressing vaginal atrophy, dryness, and dyspareunia. Multiple randomized controlled trials (RCTs) have demonstrated that a 12-week regimen of 5%–6% P. mirifica vaginal gel (standardized for isoflavonoid content) significantly elevates the Vaginal Health Index (VHI) and Vaginal Maturation Index (VMI) (Manonai et al., 2007; Sritonchai et al., 2019). Unlike systemic hormone replacement therapy (HRT), local application facilitates a rapid restoration of vaginal pH and improves the microenvironment, as evidenced by lower Nugent scores—a critical indicator for reduced bacterial vaginosis risk (Warinsiriruk et al., 2022).

From a hemodynamic perspective, Doppler ultrasound assessments have confirmed that P. mirifica gel significantly enhances vaginal arterial perfusion, evidenced by a marked decrease in the Pulsatility Index (PI) and Resistance Index (RI) (Sritonchai et al., 2020). This vascular response is likely mediated by the activation of estrogen receptors on the vaginal vascular endothelium, promoting nitric oxide-dependent vasodilation. Notably, several comparative studies indicate that P. mirifica may outperform Conjugated Equine Estrogen (CEE) cream in alleviating dysuria, possibly due to a more balanced interaction with ERβ receptors prevalent in the lower urinary tract (Suwanvesh et al., 2017).

Critically, the localized safety profile is supported by evidence that short-term use (up to 24 weeks) does not induce endometrial hyperplasia or significant changes in serum estradiol levels. However, a significant research gap remains: the majority of current studies focus on “healthy” postmenopausal cohorts. Future investigations must prioritize safety data for high-risk populations, such as breast cancer survivors with contraindications for traditional HRT, to establish P. mirifica as a validated alternative in oncological supportive care.

6.3 Impact on lipid metabolism and skeletal integrity

Emerging evidence suggests that P. mirifica exerts systemic modulatory effects on metabolic and skeletal homeostasis, although the clinical magnitude remains debated. Regarding lipid profiles, a short-term study (n = 19) demonstrated that a 100 mg/day dose of P. mirifica powder significantly elevated HDL-C and Apolipoprotein A1, while concomitantly reducing LDL-C and Apolipoprotein B (Okamura et al., 2008). This lipid-lowering effect mimics the action of endogenous 17β-estradiol, likely through the upregulation of LDL receptors in the liver. However, it is noteworthy that some subjects exhibited an elevation in triglycerides (TG)—a common side effect of oral estrogenic compounds due to their impact on hepatic lipid synthesis—necessitating caution in patients with pre-existing hypertriglyceridemia.

In terms of bone health, P. mirifica appears to function as a natural Selective Estrogen Receptor Modulator (SERM). A randomized, double-blind, placebo-controlled trial (n = 71) indicated that doses of 20–50 mg/day significantly suppressed Bone-specific Alkaline Phosphatase (BAP) levels without stimulating endometrial thickening (Manonai et al., 2008). This suggests a potent anti-resorptive effect, potentially superior to that of soy-derived isoflavones due to the unique presence of deoxymiroestrol.

Critically, the current clinical landscape for these indications is significantly limited by “methodological heterogeneity.” The discrepancy in dosages across studies (20 mg vs. 100 mg) and the lack of long-term fracture-reduction data or cardiovascular endpoint studies (e.g.,.CIMT measurements) prevent a definitive recommendation. Furthermore, the variability in the phytochemical “fingerprint” of the root powders used in these trials makes it difficult to establish a standardized therapeutic window for metabolic health.

6.4 Safety profile, toxicological risks, and pharmacological interactions

Clinical data suggest that short-term (<12 months) administration of P. mirifica is generally well-tolerated, with adverse events (AEs) typically limited to transient anemia, headache, and bloating. However, its potent estrogenic activity necessitates a rigorous appraisal of potential systemic risks.

Beyond common AEs, rare but severe cardiac risks have been identified. A critical case report highlighted a patient with a KCNQ1-T587M mutation who developed life-threatening Torsades de Pointes (TdP) following P. mirifica supplementation (Kashiwa et al., 2021). This suggests that certain isoflavones or chromenes within the plant may interfere with cardiac I_Kr potassium channels, posing a specific risk for individuals with “silent” long QT syndrome.

A large-scale survey (n = 1,200) in Japan indicated that 16.2% of users experienced estrogen-related AEs, including abnormal vaginal bleeding and mastalgia (Chiba et al., 2022). Critically, these reports often involve unregulated dietary supplements where the concentration of deoxymiroestrol—a metabolite significantly more potent than 17β-estradiol—is frequently unstandardized. This highlights a major “quality control crisis” in the P. mirifica industry, where the lack of marker-based standardization leads to unpredictable biological responses.

Although clinical data remain limited, in vitro studies suggest that P. mirifica metabolites may modulate cytochrome P450 (CYP) enzymes, particularly CYP1A1, CYP1A2, and CYP1B1. This raises a theoretical concern for patients who are concurrently receiving medications with narrow therapeutic indices or hormonal therapies for breast cancer, such as tamoxifen, because metabolic interference could potentially compromise treatment efficacy or increase toxicity.

In summary, although P. mirifica represents a promising alternative for the management of vasomotor symptoms (VMS) and genitourinary syndrome of menopause (GSM), the current evidence remains limited by small sample sizes and the absence of long-term clinically meaningful endpoints, such as breast density changes or cardiovascular events. Future research should prioritize long-term oncogenic safety trials, rigorous pharmacokinetic characterization to define the therapeutic window, and mandatory standardization of deoxymiroestrol content in all clinical research materials.

7 Discussion

Taken together, the current literature supports P. mirifica as a botanically distinctive and pharmacologically promising phytoestrogenic species; however, the overall evidence base remains uneven. Phytochemical diversity and preclinical pharmacology are relatively well documented, whereas clinical validation, pharmacokinetic characterization, long-term safety assessment, and product standardization remain underdeveloped. This imbalance explains why the literature contains substantial mechanistic and experimental promise, yet still falls short of supporting fully standardized and clinically reliable application. A clearer translational framework is therefore required to connect ethnopharmacological relevance, prioritized bioactive constituents, mechanistic pathways, and human therapeutic use.

8 Limitations of the study

While this review provides valuable insights, several limitations should be acknowledged. First, the current body of clinical evidence on P. mirifica is largely derived from small-scale and short-duration studies, leaving important gaps in the understanding of long-term safety and efficacy. Second, substantial variability among commercial P. mirifica products, driven by differences in production processes and material standardization, may influence both clinical outcomes and safety profiles. Third, the absence of comprehensive safety monitoring data, particularly from post-marketing surveillance, complicates the establishment of a clear and reliable safety profile for P. mirifica in the general population.

9 Future recommendations

To address the major translational barriers identified in this review, future research should focus on several key priorities. First, standardization strategies should be strengthened through authenticated botanical identification, control of cultivation and harvest conditions, chemical fingerprinting with prioritized marker compounds, batch-to-batch consistency testing, and bioactivity-linked quality evaluation. Second, clinical research should move toward larger, randomized, double-blind, placebo-controlled studies using well-characterized formulations, clearly defined dosages, and extended follow-up periods to better establish efficacy and long-term safety. Third, pharmacokinetic and metabolic studies should be expanded to clarify oral bioavailability, metabolite transformation, microbiota-related variability, tissue distribution, and potential herb–drug interactions. Fourth, advanced methodologies, including metabolomics, transcriptomics, proteomics, and integrated multi-omics approaches, should be more explicitly incorporated into botanical drug development in order to identify key active constituents, define mechanistic pathways, support marker discovery, and improve mechanism-guided quality control. Finally, greater regulatory harmonization will be necessary to reduce the variability of commercial P. mirifica products and to facilitate more reproducible clinical translation.

10 Conclusion

In conclusion, P. mirifica is a botanically distinctive and pharmacologically important phytoestrogenic species with considerable potential for menopause-related applications and other estrogen-responsive conditions. However, the current evidence base remains uneven: phytochemical diversity and preclinical activities are relatively well documented, whereas clinical validation, pharmacokinetic characterization, long-term safety assessment, and formulation standardization remain insufficient. Future progress will depend not only on the generation of additional data, but also on improving the quality, consistency, and translational relevance of that evidence. In particular, priority should be given to phytochemical prioritization, stronger standardization frameworks, better characterization of metabolism and tissue selectivity, rigorous long-term safety evaluation, and clinically robust trials using well-defined products. Only through such an integrated and multidisciplinary approach can the therapeutic potential of P. mirifica be more reliably advanced toward evidence-based botanical drug development.

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