Lady's Thumb

Persicaria maculosa, an annual herb in the buckwheat family (Polygonaceae), is known by a variety of common names, including Lady's Thumb, Spotted Lady's Thumb, Redshank, and Jesusplant. Native to Europe and Asia, this species has become a widespread and naturalized plant across North America and other temperate regions, often thriving in moist, disturbed soils along roadsides, riverbanks, and in agricultural fields. While frequently classified as a common weed, and in some cases an invasive species that competes with crops, this ecological resilience belies a complex and potent biochemical profile that has long been recognized in traditional medicine and is now being elucidated by modern scientific investigation.

The scientific literature presents a distinct duality in the study of P. maculosa. A significant body of contemporary research focuses on its novel pharmacological properties, particularly its capacity to act as an anti-virulence agent against opportunistic human pathogens like Pseudomonas aeruginosa. This line of inquiry positions the plant as a potential source for new therapeutic strategies to combat antibiotic-resistant infections. Concurrently, the plant holds a place in folk medicine for a range of ailments, and there is growing interest in its broader applications for human health, including its potential role in supporting women's health through the menopausal transition. The very characteristics that make P. maculosa a successful and prolific weed—its robust growth and resistance to environmental pressures—are intrinsically linked to its medicinal value. Plants produce a vast array of secondary metabolites not for primary growth, but for defense against herbivores, insects, and microbial pathogens. This chemical arsenal, rich in compounds like phenolics and flavonoids, is the source of the plant's therapeutic activities. Therefore, its "weedy" nature is not a sign of inferiority but a testament to its potent chemistry, making it an abundant and powerful, yet often overlooked, medicinal resource.

This report seeks to bridge the gap between the plant's established antimicrobial and antioxidant activities and its potential benefits for menopausal symptoms. It posits that the full therapeutic potential of P. maculosa can be understood through a multi-faceted analysis of its rich phytochemical profile. The individual compounds within the plant do not act in isolation but likely exert synergistic effects on the complex network of hormonal, inflammatory, oxidative, and structural pathways that are dysregulated during the menopausal transition. By deconstructing the plant's chemical inventory and mapping the known actions of its constituents onto the physiological challenges of menopause, a scientifically plausible framework for its efficacy emerges.

The Phytochemical Landscape of Persicaria maculosa

The therapeutic potential of Persicaria maculosa is rooted in its exceptionally rich and diverse phytochemical composition. Scientific analyses have revealed that the plant is a dense reservoir of bioactive compounds, primarily belonging to the polyphenol family. These molecules are categorized into several major classes, each contributing to the plant's overall pharmacological profile. The most well-documented constituents include phenolic acids, a wide array of flavonoids (such as flavonols and flavones), and their corresponding glycosides, where a sugar molecule is attached to the flavonoid core. Beyond these, studies of the broader Persicaria genus suggest the likely presence of other important classes of compounds, such as stilbenes, diarylheptanoids, sesquiterpenes, and triterpenes, which contribute to the wide range of biological activities observed within this plant family.

Detailed chemical analysis of an ethanol extract of P. maculosa herb identified 26 distinct phenolic compounds, providing a clear chemical blueprint of the plant. This profile is dominated by significant quantities of quinic acid, a foundational molecule in the biosynthesis of many aromatics, and quercetin-3-O-glucoside, a potent antioxidant flavonoid. Other analyses have confirmed the presence of numerous glycosyl derivatives of the key flavonoids quercetin, kaempferol, and isorhamnetin, underscoring their importance to the plant's chemistry. Furthermore, chemotaxonomic studies comparing P. maculosa with related species like P. sagittata have shown a shared presence of fundamental bioactive compounds, including gallic acid, protocatechuic acid, and quercetin, confirming a consistent phytochemical signature within the genus. The table below provides a consolidated inventory of the major phytochemicals identified in Persicaria maculosa, drawing from multiple analytical studies to create a comprehensive reference.

Category

Compound Concentrations (mg/g dw)

 

Phenolic Acids

Quinic acid

12.8

Chlorogenic acid

6.41

Gallic acid

2.47

Protocatechuic acid

0.21

Coumaric acid

0.06

Ferulic acid

0.05

p-hydroxybenzoic acid

0.04

Caffeic acid

0.02

2,5-dihydroxybenzoic acid

0.01

Syringic acid

0.01

 

Flavonoid Glycosides

Quercetin-3-O-glucoside

11.71

Hyperoside (Quercetin-3-O-galactoside)

4.93

Rutin (Quercetin-3-O-rutinoside)

2.65

Quercetin-3-O-L-rhamnoside

2.10

Kaempferol-3-O-glucoside

1.44

Apigenin-7-O-glucoside

0.22

Luteolin-7-O-glucoside

0.14

 

Flavonoids (Aglycones)

Apigenin

0.56

Epigallocatechin gallate

0.3

Quercetin

0.27

Catechin

0.19

Epicatechin

0.15

Luteolin

0.13

Naringenin

0.08

Vitexin

0.03

Myricetin

0.02

Other Flavonoids

Isorhamnetin derivatives

Not Quantified

 

Evidence-Based Therapeutic Actions of Persicaria maculosa Extracts

Scientific investigation into the pharmacological properties of Persicaria maculosa extracts has validated several of its traditional uses and uncovered novel therapeutic potentials. The research primarily highlights the plant's significant antimicrobial, antioxidant, and anti-inflammatory activities, which are directly attributable to its rich phytochemical content.

Antimicrobial and Anti-Virulence Properties

The most rigorously documented therapeutic action of P. maculosa is its ability to combat bacterial pathogens, not by killing them directly, but by disarming them. A detailed study on an ethanol extract of the plant (PEM) demonstrated potent anti-virulence activity against the opportunistic pathogen Pseudomonas aeruginosa, a bacterium notorious for its resistance to conventional antibiotics. At subinhibitory concentrations (as low as 50 µg/mL), the extract achieved a maximal inhibitory effect of approximately 50% on the formation of bacterial biofilms, which are protective slime-like colonies that shield bacteria from antibiotics and immune cells. The extract also reduced the production of pyocyanin, a toxic blue pigment and virulence factor, by 47% and completely halted the bacteria's "swarming motility," a form of coordinated movement essential for colonization and infection.

This "disarmament" strategy is fundamentally different from the mechanism of traditional antibiotics. The research revealed that the extract's primary mode of action is the disruption of quorum sensing (QS), the sophisticated chemical communication system that bacteria use to coordinate group behaviors like biofilm formation and virulence factor production. Specifically, the P. maculosa extract was found to reduce the activity of the LasR receptor, a key master regulator in the P. aeruginosa QS network. This approach of inhibiting bacterial communication rather than directly killing the cells is highly significant in an era of growing antibiotic resistance, as it may exert less selective pressure for the evolution of resistant strains. While the extract showed only weak direct bactericidal activity against several pathogens, with a high Minimum Inhibitory Concentration (MIC) of 5 mg/mL against Salmonella Enteritidis, its strength lies in modulation and regulation. This principle of modulating biological systems, rather than acting as a blunt-force agonist or antagonist, is a recurring theme in the plant's pharmacology. Further studies have broadened the plant's known antimicrobial spectrum, showing that leaf extracts also possess bacteriostatic activity against Gram-positive bacteria like Bacillus cereus, Bacillus subtilis, and Staphylococcus aureus, as well as the Gram-negative Escherichia coli.

Potent Antioxidant Activity

Multiple studies have confirmed that extracts of P. maculosa possess strong antioxidant properties, primarily due to their high concentration of total phenolics and flavonoids. Antioxidants are crucial for protecting the body's cells from damage caused by reactive oxygen species (ROS), or free radicals, which are unstable molecules generated during normal metabolism and in response to environmental stressors. Unchecked, this "oxidative stress" is implicated in aging and a wide range of chronic diseases.

The antioxidant capacity of P. maculosa has been quantified using various laboratory assays. In the 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging assay, an ethanol extract from one collection site demonstrated an SC50 value of 12.5 µg/mL, indicating that only a very small concentration of the extract was needed to scavenge 50% of the free radicals. This high level of activity is directly linked to the presence of compounds like quercetin, gallic acid, and their derivatives, which can readily donate electrons to neutralize ROS, thereby terminating damaging chain reactions. This potent antioxidant action forms a foundational pillar of the plant's overall therapeutic profile.

Anti-inflammatory and Other Reported Activities

Beyond its antimicrobial and antioxidant effects, P. maculosa is recognized for a broader suite of pharmacological activities. A comprehensive review of the Persicaria genus attributes anti-inflammatory, antifungal, and hepatoprotective (liver-protective) properties to the species. These scientifically reported activities align remarkably well with the plant's documented uses in traditional folk medicine. For instance, in Vietnamese folk remedies, the plant is used to treat arthritis, a condition characterized by inflammation. Its traditional use as a topical antiseptic for wounds is supported by its proven antimicrobial properties. Furthermore, its application in cases of jaundice points towards the hepatoprotective effects now being recognized by modern research. This convergence of traditional knowledge and scientific validation underscores the empirical wisdom developed over generations of human use and provides a strong basis for further exploring its therapeutic applications. One source also notes that the plant is a source of persicarin, a compound viewed as a candidate therapeutic for severe vascular inflammatory diseases like sepsis.

A Mechanistic Framework for the Amelioration of Menopausal Symptoms

While the provided research does not include direct clinical studies on Persicaria maculosa for the treatment of menopause, a compelling and scientifically plausible hypothesis for its efficacy can be constructed by analyzing its detailed phytochemical profile. The key lies in mapping the known pharmacological actions of its individual constituent compounds onto the complex physiological and symptomatic cascade of the menopausal transition. The plant's benefits appear to stem not from a single mechanism, but from a multi-pronged approach involving phytoestrogenic modulation, specific support for bone health, systemic reduction of inflammation and oxidative stress, and direct support for neurological well-being.

The Menopausal Transition: A Cascade of Physiological Change

Menopause is defined by the permanent cessation of menstruation resulting from the loss of ovarian follicular activity. The decline in the production of the primary female hormone, estrogen, triggers a cascade of systemic effects that extend far beyond the reproductive system. The most well-known of these are vasomotor symptoms, such as hot flashes and night sweats. However, the loss of estrogen also leads to urogenital atrophy, causing vaginal dryness and discomfort; accelerates the loss of bone mineral density, leading to osteoporosis; alters lipid profiles, increasing the risk of cardiovascular disease; and impacts the central nervous system, contributing to mood swings, anxiety, insomnia, and cognitive changes often described as "brain fog".

Many plant-based approaches to managing these symptoms rely on compounds known as phytoestrogens. These are non-steroidal plant molecules that possess a structural similarity to the human hormone 17β-estradiol. This similarity allows them to bind to the body's estrogen receptors (ERs), of which there are two main types: estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). Unlike endogenous estrogen, many phytoestrogens exhibit a preferential binding affinity for ERβ. Because ERα and ERβ are distributed differently throughout the body's tissues and can trigger different downstream effects, phytoestrogens can act as natural Selective Estrogen Receptor Modulators (SERMs). In a low-estrogen environment like menopause, they can provide a weak, buffering estrogenic effect, potentially alleviating symptoms like hot flashes without over-stimulating tissues like the breast or endometrium, which are rich in ERα.

The Phytoestrogenic Arsenal of Persicaria maculosa

Persicaria maculosa is rich in several well-characterized flavonoids that are known to possess phytoestrogenic activity. This chemical arsenal provides a direct mechanism for modulating the hormonal imbalance that drives many menopausal symptoms.

Quercetin: Found in significant quantities in P. maculosa, both as an aglycone and in various glycoside forms, quercetin is a well-established phytoestrogen. Beyond its ability to interact with estrogen receptors, it is an exceptionally potent antioxidant, demonstrating a capacity to protect low-density lipoprotein (LDL) from oxidation that is far superior to that of other phytoestrogens like genistein and even estradiol itself. This is particularly relevant post-menopause, when the risk of cardiovascular disease increases partly due to unfavorable changes in lipid profiles.

Kaempferol: Also present as a glycoside in P. maculosa, kaempferol is explicitly identified in the literature as a phytoestrogen with potential use as an alternative to conventional hormone replacement therapy (HRT). Its ability to interfere with the estrogen signaling pathway allows it to exert estrogen-like effects in the body, which can help mitigate symptoms arising from estrogen deficiency.

Luteolin: This flavonoid, present in P. maculosa, is described as a potent estrogen agonist. Its strong ability to activate estrogenic pathways suggests it could play a significant role in compensating for the sharp decline in endogenous estrogen levels during menopause.

Apigenin: Perhaps one of the most compelling compounds in the context of menopause, apigenin is present in P. maculosa and has been the subject of highly relevant mechanistic research. A landmark study demonstrated that apigenin directly addresses xerostomia (dry mouth), a common menopausal complaint, in an ovariectomized mouse model (a standard preclinical model for post-menopause). The study found that apigenin activates ERα signaling in human salivary gland cells, which in turn upregulates the expression of aquaporin-5 (AQP5), a crucial water channel protein responsible for saliva secretion. This restored saliva flow in the estrogen-deficient mice. This finding provides a direct, powerful mechanistic link between a specific phytochemical in P. maculosa and the alleviation of a specific menopausal symptom (dryness), with strong implications for its potential to also alleviate urogenital dryness.

Beyond Direct Estrogenic Action: A Multifactorial Support System

The therapeutic potential of P. maculosa in menopause extends well beyond simple estrogenic mimicry. Its phytochemicals provide a comprehensive support system that addresses other critical long-term health risks and symptoms associated with this life stage.

Mitigating Long-Term Risks: Bone Health: Osteoporosis is a major long-term consequence of menopause. Remarkably, a key flavonoid derivative found in P. maculosa, isorhamnetin, has been shown to directly combat this process. A pivotal study using the ovariectomized rat model of postmenopausal osteoporosis found that treatment with isorhamnetin significantly ameliorated bone loss. It improved bone mineral content and density, uterine weight, and serum biomarkers of bone turnover. The mechanism was shown to involve the modulation of critical bone signaling pathways, including the RANKL/OPG axis which controls bone resorption, and the BMP-2/Runx2 pathway which governs bone formation. Additionally, isorhamnetin significantly reduced levels of pro-inflammatory cytokines like TNF-α and IL-6, which are known to drive bone loss. This provides a powerful, non-estrogenic mechanism by which P. maculosa can help protect against a major chronic disease of aging in women.

Combating Systemic Stress: Antioxidant and Anti-inflammatory Effects: The menopausal transition is associated with a systemic shift towards a pro-inflammatory state and increased oxidative stress, which contribute to a wide range of symptoms and increase the risk of chronic disease. The potent antioxidant and anti-inflammatory properties of P. maculosa, conferred by its rich blend of phenolics and flavonoids, directly counteract these underlying processes. This systemic action can help alleviate generalized symptoms like joint pain and fatigue, while also contributing to the reduction of long-term cardiovascular risk.

Supporting Neurological and Psychological Well-being: The neurological and psychological symptoms of menopause, including anxiety, insomnia, and cognitive fog, can be profoundly disruptive. The phytochemicals in P. maculosa offer direct support in this domain. Apigenin is well-known for its anxiolytic (anxiety-reducing) and sedative properties, which can promote better sleep. Quercetin has demonstrated significant neuroprotective effects, helping to shield brain cells from oxidative stress and inflammation. These actions directly map onto common menopausal complaints, suggesting the plant can help stabilize mood and support cognitive function during this transition.

The Synergy Hypothesis: The Whole is Greater than the Sum of its Parts

The efficacy of Persicaria maculosa for menopausal symptoms is unlikely to be attributable to any single compound. Instead, it is the result of the synergistic interplay of its diverse phytochemical constituents. This concept of synergy, where the combined effect of multiple compounds is greater than the sum of their individual effects, is a cornerstone of herbal medicine. In the case of P. maculosa, one can envision a scenario where the phytoestrogenic flavonoids (quercetin, kaempferol, luteolin) provide a gentle buffer for vasomotor symptoms, while isorhamnetin specifically targets bone-remodeling pathways to prevent osteoporosis, apigenin restores moisture to mucosal tissues, and the full spectrum of phenolics works to quell systemic inflammation and oxidative stress.

This principle of synergy is mirrored in the plant's anti-virulence activity, where the whole extract was found to be more effective than its dominant isolated constituents. A similar dynamic is likely at play in its effects on the complex, multi-system changes of menopause. However, this also introduces a critical note of caution. Research has shown that while certain compounds may be beneficial as part of a whole-plant extract, their effects can change when consumed as high-dose, isolated supplements. For example, one study found that while injected apigenin was protective, pure apigenin ingested orally by rats on progestin therapy actually aggravated mammary tumor growth. This highlights the profound importance of the natural plant matrix, which may contain other compounds that buffer, modulate, or alter the metabolism of a single active ingredient, potentially making the whole-plant form both safer and more effective.

The following table summarizes the proposed multi-target mechanisms by which the key phytochemicals in Persicaria maculosa may alleviate the symptoms and health risks associated with menopause.

Phytochemical

Target Symptom/Condition

Proposed Mechanism of Action

Evidence

Apigenin

Urogenital/Oral Dryness (Xerostomia)

Activates Estrogen Receptor Alpha (ERα) signaling, leading to the upregulation of aquaporin-5 (AQP5) water channels in epithelial cells.

Isorhamnetin

Osteoporosis Risk / Bone Density Loss

Modulates key bone signaling pathways (RANKL/OPG, BMP-2/Runx2) to balance bone resorption and formation; reduces inflammatory cytokines (TNF-α, IL-6).

Quercetin, Kaempferol, Luteolin

Vasomotor Symptoms (Hot Flashes), Mood Instability

Phytoestrogenic; bind to and modulate Estrogen Receptors (ERα/ERβ), providing a weak estrogenic buffer effect in a low-estrogen state.

All Phenolics (Gallic Acid, Chlorogenic Acid, etc.)

Systemic Inflammation, Cardiovascular Risk, Cognitive Fog

Potent antioxidant activity (scavenging of Reactive Oxygen Species) and broad anti-inflammatory actions.

Concluding Analysis and Future Directions

The collective evidence drawn from the phytochemical analysis and pharmacological studies of Persicaria maculosa and its constituent compounds allows for the construction of a robust, mechanistically plausible hypothesis for its efficacy in alleviating menopausal symptoms. While direct clinical trials on P. maculosa for menopause are conspicuously absent from the available research, the convergence of data points to a multi-target therapeutic potential. The plant appears to function not as a simple hormonal replacement, but as a sophisticated biological response modifier, addressing the menopausal transition through a combination of gentle phytoestrogenic action, targeted bone protection, systemic anti-inflammatory and antioxidant support, and direct neuro-supportive effects.

The primary limitation of this analysis is the inferential nature of its central conclusion. The hypothesis, while scientifically grounded, is built by connecting the known actions of isolated compounds to the symptoms of menopause, rather than from direct studies of the whole-plant extract for this specific application. Furthermore, the cautionary findings regarding the oral ingestion of isolated apigenin supplements in combination with progestin therapy highlight a critical area of uncertainty. This underscores that the safety and efficacy of a whole-plant extract, with its complex chemical matrix and potential for synergistic or buffering interactions, cannot be fully predicted from the study of a single, high-dose compound. The metabolism of these compounds upon ingestion and their interaction with other medications, particularly hormone therapies, remains a significant knowledge gap.

To validate the therapeutic potential of Persicaria maculosa for menopause management, a structured program of future research is required. The logical progression of such a program would include:

Preclinical In Vivo Studies: Utilizing established ovariectomized rodent models, which mimic the postmenopausal state, to test the effects of a standardized, whole-plant P. maculosa extract. These studies should assess a comprehensive range of endpoints, including vasomotor responses (e.g., tail skin temperature), bone mineral density, serum lipid profiles, cognitive function, and markers of inflammation and oxidative stress.

Pharmacokinetic and Metabolism Studies: Investigating how the key phytochemicals in P. maculosa are absorbed, distributed, metabolized, and excreted when consumed as a whole extract. This is essential to understand bioavailability and to clarify the concerns raised by studies on isolated compounds.

Human Clinical Trials: The ultimate validation would require well-designed, randomized, placebo-controlled clinical trials in peri- and postmenopausal women. Such trials would need to assess the efficacy of a standardized P. maculosa extract on validated scales for menopausal symptoms (e.g., hot flash frequency and severity, quality of life metrics) as well as its safety profile and effects on biomarkers for bone and cardiovascular health.

In conclusion, Persicaria maculosa emerges from this analysis not as a simple weed, but as a promising candidate for a natural, multi-target therapeutic for the management of menopausal symptoms and the mitigation of associated long-term health risks. Its rich, synergistic blend of phytoestrogens, bone-protective flavonoids, antioxidants, and anti-inflammatory agents presents a compelling case for its utility. However, this potential must be rigorously investigated through preclinical and clinical research before its place in evidence-based medicine can be firmly established.

Works cited

1. Lady Thumbs - Eat The Weeds and other things, too, https://www.eattheweeds.com/lady-thumbs/
2. Persicaria maculosa - Nonindigenous Aquatic Species - USGS.gov, https://nas.er.usgs.gov/queries/greatlakes/FactSheet.aspx?SpeciesID=2666&Potential=N&Type=0&HUCNumber=All%20Great%20Lakes
3. Persicaria maculosa - Wikipedia, https://en.wikipedia.org/wiki/Persicaria_maculosa
4. Persicaria maculosa (Lady's-thumb) - Minnesota Wildflowers, https://www.minnesotawildflowers.info/flower/ladys-thumb
5. Lady's Thumb | Weed identification guide for Ontario crops, https://www.ontario.ca/document/weed-identification-guide-ontario-crops/ladys-thumb
6. Anti-Virulence Potential and In Vivo Toxicity of Persicaria maculosa ..., https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221584/ 
7. Morphological, anatomical and antibacterial characteristics of Persicaria maculosa Gray plants growing in Lang Sen Wetland Reser - GSC Online Press, https://gsconlinepress.com/journals/gscbps/sites/default/files/GSCBPS-2021-0356.pdf
8. Relationship: Menopause and Polygonum (unspecified) - Caring Sunshine, https://caringsunshine.com/relationships/relationship-menopause-and-polygonum-unspecified/
9. Phenolic Fingerprinting, Antioxidant, and Deterrent Potentials of Persicaria maculosa Extracts - PubMed, https://pubmed.ncbi.nlm.nih.gov/32635342/
10. An Update on Phytochemicals and Pharmacological Activities of the ..., https://pmc.ncbi.nlm.nih.gov/articles/PMC8512787/
11. An Update on Phytochemicals and Pharmacological Activities of the Genus Persicaria and Polygonum - MDPI, https://www.mdpi.com/1420-3049/26/19/5956
12. Chemical Constituents of Persicaria sagittata (L.) H.Gross ..., https://brieflands.com/articles/jjnpp-64788
13. Phenolic Fingerprinting, Antioxidant, and Deterrent Potentials of Persicaria maculosa Extracts - PMC, https://pmc.ncbi.nlm.nih.gov/articles/PMC7411858/
14. Phytochemical profiling, antioxidant, enzymatic inhibitory, and antibacterial activities of Wigandia ecuadorensis - Frontiers, https://www.frontiersin.org/journals/plant-science/articles/10.3389/fpls.2024.1481447/full
15. phytoestrogen quercetin impairs: Topics by Science.gov, https://www.science.gov/topicpages/p/phytoestrogen+quercetin+impairs
16. Antioxidant activity of Persicaria maculosa extracts (N = 3/extract) - ResearchGate, https://www.researchgate.net/figure/Antioxidant-activity-of-Persicaria-maculosa-extracts-N-3-extract_tbl2_342721982 
17. Phytoestrogens and Their Health Effect - PMC, https://pmc.ncbi.nlm.nih.gov/articles/PMC6390141/
18. Polygonatum sibiricum improves menopause symptoms by regulating hormone receptor balance in an ovariectomized mouse model - PubMed, https://pubmed.ncbi.nlm.nih.gov/36076523/
19. Phytoestrogens in Postmenopause: The State of the Art from a Chemical, Pharmacological and Regulatory Perspective - PubMed Central, https://pmc.ncbi.nlm.nih.gov/articles/PMC3963458/
20. Estrogenic response for kaempferol in the recombinant yeast... | Download Scientific Diagram - ResearchGate, https://www.researchgate.net/figure/Estrogenic-response-for-kaempferol-in-the-recombinant-yeast-assay-Different_fig8_257464772 21.
21. Phytoestrogens possess a weak antioxidant activity on low density lipoprotein in contrast to the flavonoid quercetin in vitro in postmenopausal women - PubMed, https://pubmed.ncbi.nlm.nih.gov/15799611/
22. Anti-cancer Effect and Underlying Mechanism(s) of Kaempferol, a Phytoestrogen, on the Regulation of Apoptosis in Diverse Cancer Cell Models, https://pmc.ncbi.nlm.nih.gov/articles/PMC3936174/
23. The Flavone Luteolin, an Endocrine Disruptor, Relaxed Male Guinea Pig Gallbladder Strips | Kline | Gastroenterology Research, https://www.gastrores.org/index.php/Gastrores/article/view/1142/1167
24. Endocrine Disrupting Activities of the Flavonoid Nutraceuticals Luteolin and Quercetin | Request PDF - ResearchGate, https://www.researchgate.net/publication/247772261_Endocrine_Disrupting_Activities_of_the_Flavonoid_Nutraceuticals_Luteolin_and_Quercetin
25. Apigenin, a Single Active Component of Herbal Extract, Alleviates Xerostomia via ERα-Mediated Upregulation of AQP5 Activation - Frontiers, https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.818116/full
26. Isorhamnetin ameliorates ovariectomy-induced osteoporosis in female rats by regulating the receptor activator of nuclear factor kappa B ligand, osteoprotegerin, bone morphogenetic protein 2 and runt-related transcription factor 2 signaling pathway - PMC - PubMed Central, https://pmc.ncbi.nlm.nih.gov/articles/PMC12246561/
27. Apigenin benefits, dosage, and side effects - Examine.com, https://examine.com/supplements/apigenin/
28. Apigenin Supplements: Benefits, Side Effects, and Dose - Hone Health, https://honehealth.com/edge/apigenin-supplements/ 
29. Women prescribed hormone therapy should use caution when taking apigenin supplement, https://www.sciencedaily.com/releases/2013/11/131120155213.htm