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Endometriosis

Endometriosis affects at least 11% of women (and people assigned female at birth) worldwide [x] and is a chronic and debilitating condition characterized by the growth of endometrial tissue outside the uterus, leading to pelvic pain, infertility, and other symptoms. Although retrograde menstruation is generally accepted as the cause of endometriosis, most women experience retrograde menstruation, yet only 10% develop endometriosis, suggesting that other factors contribute to its development [x].

The exact cause of endometriosis is not fully understood, but it is believed to be influenced by retrograde menstruation, estrogen metabolism, inflammation, metal homeostasis, and the microbiome. There is currently no cure for endometriosis, and treatment options are often ineffective or have grave side effects. Thus, further exploring the etiology and pathophysiology of endometriosis and its microbiome signature is crucial for developing effective diagnostic tools and improving targeted treatments.

Microbiome Involvement in Estrogen Metabolism 

The microbiome modulates estrogen metabolism through the estrobolome, a collection of genes in the gut microbiome responsible for encoding estrogen-metabolizing enzymes.

The interplay between gut and genital microbiota, along with the estrobolome, has significant implications for endometriosis, infertility, and chronic pelvic pain (CPP). Within this intricate system, a critical process involves the deconjugation of estrogen from glucuronic acid, facilitated by specific gut bacteria such as Escherichia coli, Bacteroides fragilis, and Streptococcus agalactiae possessing the β-Glucuronidase enzyme, which are elevated in patients with endometriosis.

This microbial activity can have profound effects on circulating estrogen levels. Changes in the composition of gut microbiota and the estrobolome can perturb hormonal balance, potentially driving estrogen-mediated conditions. These alterations in estrogen levels can lead to a cascade of consequences, including inflammation, hormonal dysregulation, changes in cellular function, and increased angiogenesis. These factors collectively contribute to conditions such as endometriosis and infertility.

Thus, microbiome dysbiosis can lead to an imbalance in estrogen metabolism, contributing to the development of endometriosis. The dysbiosis seen in endometriosis is thought to be both causative and a consequence of the pathogenesis [x, x, x].

Metal Homeostasis in Endometriosis-Associated Bacteria

Transition metals, including iron, zinc, copper, manganese, and others, play a crucial role in the enzymatic machinery of organisms. Bacteria encounter the challenge of navigating environments where metal levels can vary significantly. To address this challenge, bacteria must effectively maintain metal homeostasis, encompassing the acquisition, balancing, and regulation of their internal pools of transition metals. This process is essential to ensure metal-dependent enzymes receive the appropriate metal cofactors.

Bacteria have developed regulatory mechanisms to achieve metal homeostasis that enable them to sense metal concentrations and adjust their gene expression accordingly. These mechanisms allow bacteria to adapt to conditions of metal limitation or excess. The ability of bacteria to manage their transition metal requirements effectively is fundamental to their survival and adaptability across diverse environments. It reflects the complexity of microbial physiology and the evolutionary pressures that have shaped their metal acquisition and homeostasis strategies.

Understanding these intricate mechanisms is vital for elucidating bacterial biology and holds practical implications for areas such as antimicrobial drug development. Disrupting metal homeostasis can be a potential target for combating bacterial infections, making it a subject of significant interest in microbiology and therapeutics. However, the discussion on metal homeostasis and its involvement in endometriosis pathophysiology primarily focuses on the role of iron. While there is ongoing research in this area, some key points related to metal homeostasis and endometriosis can be summarized as follows:

Iron Overload: Systematic reviews confirm that iron levels are abnormally high in endometriosis lesions. Shedding light on one aspect of the condition’s pathophysiology, this high iron content is attributed to the repeated episodes of bleeding and retrograde menstruation that occur in individuals with endometriosis. When red blood cells break down within these lesions, the iron they contain is released into the pelvic cavity. This can disrupt iron homeostasis within the pelvic environment [x].

Pathogenic Bacterial Species: Pathogenic bacterial species associated with iron overload often possess specific mechanisms for iron acquisition. While research has explored the potential relationship between certain bacterial species and endometriosis, the direct connection between iron overload, these bacteria, and endometriosis is complex and still an area of ongoing investigation.

Complex interactions: The interplay between iron homeostasis, inflammation, local microbiome disruption, and endometriosis is complex and multifactorial. Iron-induced inflammation and oxidative stress may also create an environment conducive to the survival and growth of endometriotic lesions.

Understanding the role of iron and metal homeostasis in endometriosis could have therapeutic implications. Exploring strategies to modulate iron levels, including iron chelation therapy, has been considered as a potential approach to alleviate symptoms, influence the microbiome, and mitigate disease progression in endometriosis. Understanding these mechanisms is essential for developing strategies to combat infection and inflammation in endometriosis, underscoring the importance of continued research into bacterial pathogenesis, microbiome signatures associated with endometriosis, and host-pathogen interactions.

Microbiome Signature of Endometriosis

The microbiome’s role in endometriosis is an area of growing interest and research, with studies exploring how changes in the vaginal, gut, and reproductive tract microbiota may relate to the disease’s onset and progression. This overview consolidates various findings to present a more coherent and cohesive understanding of the microbiome’s role in endometriosis:

1. Vaginal Microbiome as a Predictor of Endometriosis Stage:

The vaginal microbiome might have potential as a predictive tool for the stage of endometriosis, as indicated in a pilot study titled “The Vaginal Microbiome as a Tool to Predict rASRM Stage of Disease in Endometriosis” [x].

2. Alterations in Microbiota in Endometriosis:

Endometriosis has been associated with changes in the gut and reproductive tract microbiota. These alterations often involve decreased beneficial probiotics and increased pathogenic microbes, leading to significant estrobolomic and metabolomic changes. Animal studies also indicate a bidirectional relationship between gut microbiota and the development and progression of endometriosis [x].

3. Role of Lactobacilli in Vaginal Health:

The vaginal microbiome is the least diverse compared to the complexity of microbiomes in other parts of the body. It is predominantly composed of Lactobacillus species, which play a crucial role in maintaining an acidic environment in the vagina. This acidic pH is instrumental in inhibiting the growth of other bacterial and fungal species. Lactobacilli achieve this by fermenting glycogen into lactic acid, keeping the vaginal pH around 4.4 to 4.6, thus ensuring a protective milieu against pathogenic organisms. Additionally, some strains also produce a bactericidal peptide known as bacteriocin, and/or hydrogen peroxide, both of which inhibit the growth of harmful microorganisms [x].

4. Microbiome in Women with Endometriosis:

In women with endometriosis, studies have observed a depletion of Lactobacillus in the cervicovaginal microbiome and an overgrowth of bacteria such as those associated with bacterial vaginosis. This imbalance has been linked to endometriosis and infertility in the majority (23/28) of studies [x]

5. Cervical Microbiome Changes in Endometriosis:

The cervical microbiome in endometriosis patients tends to exhibit increased Firmicutes and decreased Actinobacteria and Bacteroidetes [x].

6. Diverse Cervical Microbiome and Clinical Outcomes:

A more diverse cervical microbiome is associated with better clinical outcomes. However, an increased abundance of Lactobacillus in combination with increased Streptococcus and decreased Dialister is associated with advanced stages of endometriosis, high CA125 levels, severe pain, and infertility [x].

7. Minority Microbiota and Endometriosis:

Microorganisms such as Acidovorax, Devosia, Methylobacterium, Phascolarctobacterium, and Streptococcus have been implicated in the etiology of endometriosis. These bacteria modulate estrogen metabolism and inflammation, contributing to the disease [x].

8. Bacterial Species and Endometriosis:

The increased presence of bacterial species like Streptococcus spp., Proteobacteria, Enterobacteriaceae, and Escherichia coli in various microbiome sites has been noted in endometriosis, suggesting a complex interplay between these bacteria and the disease [x].

9. Fusobacterium Nucleatum and Endometriosis:

A recent study using fluorescence in situ hybridization assay found that 64% of women with endometriosis have Fusobacterium nucleatum infection in their endometrial tissues, compared to only 7.1% of women without endometriosis. This finding indicates a significant association of F. nucleatum with endometriosis. This infection was also associated with increased M2 macrophage infiltration and elevated transforming growth factor (TGF) levels in the endometrial tissues [x].

10. Microbiome Differences in Endometriosis vs Healthy Controls:

There is an increased prevalence of Streptococcus in the endometrium and cervix of women with endometriosis, along with higher concentrations of bacterial endotoxins in menstrual blood. The presence of E. coli in menstrual blood of women with endometriosis compared to control groups suggests a potential contribution to the development of the condition. Increased levels of bacterial endotoxin in menstrual and peritoneal fluids of women with endometriosis may promote the growth of the condition via Toll-like receptor 4-mediated pathways [x, x].

11. β-Glucuronidase Expression

No differences were found in α and β diversity between patients with endometriosis and controls. However, immunohistochemistry analysis showed higher β-glucuronidase expression in bowel lesions and uterosacral ligament lesions compared to the normal endometrium (p<0.01) [x].

In summary, these findings collectively suggest a significant and complex relationship between the microbiome and endometriosis, highlighting the potential role of specific bacterial species and microbial imbalances in the disease’s pathogenesis and progression.

BacteriaMicrobiome Signatures relative to Healthy Controls
Streptococcus spp. ⬆Several reviews have found that Streptococcus is increased in endometriosis. [x, x,]

Streptococcus spp. possess genes for iron acquisition, such as siderophores [x].

Lactobacillus
⬇ ⬆

Lactobacillus spp. dominance in the cervicovaginal microbiome is characteristic of cervicovaginal health. Bacterial vaginosis-associated bacteria and Lactobacillus depletion in the cervicovaginal microbiome were associated with endometriosis and infertility in the majority (23/28) of studies.  [x]

However, one study found that an increased abundance of Lactobacillus combined with increased Streptococcus and decreased Dialister was associated with advanced endometriosis stages, high CA125 levels, severe pain, and infertility [x, x].

Bacteroides fragilis⬆
Bacteroides fragilis is increased in endometriosis. [x,x]

Bacteroides fragilis removes iron from heme and releases free protoporphyrin IX in the periplasmic space. Transport of heme derived iron requires the presence of the membrane ferrous iron transporter FeoAB and the CobN-like chelatases BtuS1 and BtuS2 [x].

Bacteroides fragilis, specifically the enterotoxigenic strains (ETBF), are known to be associated with diarrheal disease in humans. ETBF strains of B. fragilis produce a heat-labile toxin known as B. fragilis toxin (BFT) or fragilysin. This toxin has been implicated in causing diarrheal symptoms by disrupting the intestinal epithelial barrier and inducing inflammation in the gut [x].

Dialister ⬇
Decreased [x]

Human Papilloma Virus HPV ⬆

Additionally, the peritoneal fluid of women with endometriosis contains higher concentrations of bacterial endotoxins and an increased incidence of mollicutes and HPV viruses [x] .


Streptococcus agalactiae⬆
[x,x]


Atopobium ⬇

One study found the complete absence of Atopobium in the vaginal and cervical microbiota of the endometriosis group [x].

Gardnerella ⬆
Increased [x].

E. coli ⬆

Studies have found that Escherichia coli (E. coli) is increased in endometriosis [x]. E. coli expresses β-glucuronidase. This enzyme, which belongs to the family-2 glycosyl hydrolase, is encoded by the uidA gene in E. coli, and can impact various physiological and pathological processes in the human body. In endometriosis, the expression of β-glucuronidase by E. coli might have several implications.

For example, β-Glucuronidase can deconjugate estrogen metabolites in the gut, leading to reabsorption of estrogens back into circulation. Estrogen plays a crucial role in the pathophysiology of endometriosis, as it promotes the growth and maintenance of endometrial tissue. Elevated levels of circulating estrogen appear to exacerbate endometriosis symptoms or contribute to the disease’s progression [x].

Of note, increased intestinal permeability could facilitate the translocation of bacteria such as E. coli from the gut to the pelvic cavity. This translocation might contribute to the inflammatory environment and microbiome signature typical of endometriosis.

Some strains of E. coli, particularly those with virulence factors such as certain adhesins and siderophores, can influence iron homeostasis and may be associated with iron overload.

The presence of multiple transition metal acquisition systems in pathogenic E. coli indicates the importance of iron and other metal ions in the context of bacterial infections. These acquisition systems may involve siderophores, which are molecules produced by bacteria to scavenge iron from the host environment. Siderophores have been found to serve multiple roles, including binding to copper and producing inhibitors of iron uptake by competing bacterial species [x].

One intriguing aspect is how pathogenic E. coli access essential nutrients like iron while concurrently protecting themselves from the potential toxic effects of excess metal ions. This reflects the adaptability and sophistication of pathogenic bacteria in their strategies for survival and proliferation within the host [x].


Fusobacterium Nucleatum ⬆

The question of whether Fusobacterium nucleatum expresses β-glucuronidase specifically is not directly addressed in the literature. However, there is extensive research on the role of F. nucleatum in various systemic diseases and its mechanisms of pathogenicity. 

Fusobacterium nucleatum is a gram-negative, anaerobic bacterium commonly found in the oral cavity and has been associated with various health conditions. It plays a significant role in oral diseases and has been implicated in systemic diseases such as cardiovascular diseases, adverse pregnancy outcomes, and several cancer types, including breast cancer [x,x,x,x,x,x] .

In terms of its pathogenic mechanisms, F. nucleatum has been found to influence the abundance of genes involved in bacterial chemotaxis, flagellar assembly, and lipopolysaccharide (LPS) biosynthesis, particularly in oral squamous cell carcinoma (OSCC) [x] .

Additionally, F. nucleatum’s role in cancer development has been explored, with studies indicating its potential in modulating immune responses and influencing cancer cell proliferation and tumor development​ [x,x,x] .


Bifidobacterium ⬆
Increased [x].

Blautia ⬆
Increased [x].

Dorea ⬆
Increased [x].

Shigella ⬆

Researchers found a unique genetic sequence in ectopic endometriotic tissue, which showed homology to Shigella DNA. This suggests a possible role for bacterial infection in the etiology of endometriosis. The similarity in pathogenesis between shigellosis and endometriosis, including aspects like inflammation, tissue destruction, and fibrosis, supports this hypothesis. This novel “Infection hypothesis” proposes that Shigella or similar organisms might trigger immunological changes leading to endometriosis [x].

More recent case-control studies have demonstrated the presence of dysbiosis in women with endometriosis. In one of these cases, a case of stage 3 and 4 endometriosis was associated with dysbiosis characterized by an increased Gardnerella-, Escherichia-, and Shigella-type bacteria the mucous membrane of the cervix, while there was a complete absence of Atopobium vaginae bacteria in the vagina and neck of the uterus [x]

Ralstonia
Increased [x].

Estrogen-Metabolizing Bacteria

The intricate relationship between gut and genital microbiota, the estrobolome, and female reproductive health conditions such as endometriosis, infertility, and chronic pelvic pain is a topic of significant interest and complexity. The estrobolome constitutes a specialized collection of genes within the gut microbiome that are responsible for the metabolism of estrogen. This includes enzymes that are critical for the deconjugation of estrogen from glucuronic acid. The presence of specific gut bacteria, notably Escherichia coli, Bacteroides fragilis, and Streptococcus agalactiae, plays a pivotal role in this process.

Alterations in the gut microbiota and estrobolome can lead to significant changes in circulating estrogen levels. Such changes are instrumental in disrupting the hormonal balance, which in turn can contribute to various estrogen-mediated conditions. This hormonal imbalance is not just confined to systemic effects but also influences local environments such as the cervicovaginal mucosa. The disruption in the hormonal milieu can lead to inflammation, hormonal dysregulation, alterations in cellular proliferation and apoptosis, and an increase in angiogenesis. These changes are particularly relevant in the context of conditions like endometriosis and infertility, where hormonal regulation plays a key role.

The phenomenon of gut dysbiosis, which refers to a shift from a diverse and balanced gut microbiome to a less diverse and potentially harmful one, has significant implications for female reproductive health. This dysbiosis can lead to an increase in systemic inflammation and immune cell trafficking, affecting the gut and the cervicovaginal microenvironment. In a healthy state, a diverse gut microbiome maintains homeostatic estrogen levels and minimizes inflammation, whereas gut dysbiosis can increase circulating estrogen levels and pro-inflammatory cytokines. These changes can result in menstrual cycle irregularities and increased stimulation of endometrial tissue, leading to conditions like chronic pelvic pain and endometriosis, and potentially contributing to reproductive system cancers.

Furthermore, the impact on cervicovaginal health is profound. Estrogen influences the cervicovaginal environment by increasing glycogen availability, which promotes the dominance of Lactobacillus species, crucial for maintaining a healthy cervicovaginal pH and reducing inflammation. However, an excess of estrogen, possibly resulting from gut dysbiosis, can disrupt this delicate balance, leading to conditions characterized by an altered vaginal microbiome and increased pH, commonly associated with various cervicovaginal diseases.

In summary, the interplay between gut and genital microbiota, the estrobolome, and hormonal regulation is a critical area of research that offers valuable insights into the pathogenesis of various female reproductive health conditions. Understanding these relationships opens up potential avenues for novel interventions and therapeutic strategies targeting the microbiome and hormonal balance in the treatment of conditions like endometriosis, infertility, and chronic pelvic pain.

Microbiome Manipulations for Endometriosis

Diet for Endometriosis

It is speculated that regulation of the gut microbiota through diet may help prevent endometriosis. Research also suggests that dietary choices can play a significant role in managing symptoms of Endometriosis. Several key dietary principles have been identified:

Reduction of Inflammatory Foods: Incorporating anti-inflammatory foods and supplements while reducing the intake of inflammatory foods is crucial. A diet high in fat, particularly from red meat and dairy products, has been associated with worsening endometriosis symptoms [x][x][x].

Predominantly Vegetarian Diet: Research suggests that a diet largely composed of vegetarian foods can help reduce or even eliminating the symptoms of endometriosis [x].Women who consume a large amount of fruits, vegetables, dairy products, and omega-3 fatty acids have an attenuated risk of endometriosis [x].

Omega-3 polyunsaturated fatty acids were found to attenuate the inflammation in a mouse model of endometriosis [x]. In addition, women who consume a large amount of ω-3 polyunsaturated fatty acids have a lower risk of developing endometriosis [x].

Enhancing Detoxification Mechanisms: Detoxification of estrogen is important for reducing endometriosis symptoms. Cruciferous vegetables (such as broccoli, cauliflower, kohlrabi, cabbage, and Brussels sprouts) are high in indole-3-carbinol, a compound that assists in metabolizing estrogen in the liver. This is critical in eliminating xenoestrogens and reducing the radical load [x].

Beneficial Compounds in Foods:

Quercetin: Found in apples, onions, garlic, leeks, citrus, cherries, red wine, and peppers, this bioflavonoid stimulates the immune system and acts as an antioxidant [x].

Curcumin: The yellow pigment in turmeric, curcumin is widely recognized for its antioxidant properties and anti-inflammatory benefits [x].

Isoflavones: Found in soy, these compounds have been shown to regress endometrial lesions in animal models and prevent their development [x].

Flax Seeds and Flax Seed Oil: Both are beneficial due to their alpha-linolenic acid and lignans, which possess anti-inflammatory effects [x].

Reducing or Eliminating Certain Foods: High sugar intake and caffeine should be greatly reduced or eliminated. These foods are associated with increased levels of estrogen in both human and animal models [x, x, x, x], though meta-analyses refute the connection with caffeine [x]. Trans-unsaturated fatty acids and red meat can also increase the risk of endometriosis [x].

Dioxin Exposure Through Diet: While most meat and milk samples tested for dioxin were considered below acceptable levels, for those suffering from endometriosis, it is advisable to avoid dioxin-contaminated foods [x, x, x].

In effect, a comprehensive dietary approach involving reducing inflammatory foods, incorporating specific beneficial compounds, and avoiding certain food items can effectively manage the symptoms of endometriosis.

Supplements for Endometriosis

Increasing awareness of the adverse effects and toxicity of synthetic medications has led to the increasing inclusion of natural sources and alternative treatment options in the human healthcare system [x]. In fact, traditional therapies provide primary healthcare to around 80% of the global population. Further, many contemporary medications used to cure ailments in humans and animals have botanical bases [x], while natural sources account for over 70% of medication ingredients [x].


Lactoferrin


Research on prebiotics that specifically improve the population of Lactobacillus in the female reproductive tract is limited. However, a study highlighted in the PubMed article “Antimicrobial and Prebiotic Activity of Lactoferrin in the Female Reproductive Tract: A Comprehensive Review” suggests that lactoferrin, a protein found in milk and other secretions, may have prebiotic activities.

Lactoferrin can potentially support the growth of beneficial bacteria like Lactobacillus in the female reproductive tract, contributing to its health. This indicates that lactoferrin might play a role in maintaining a healthy balance of microbiota in the genital tract, and could prove useful in the treatment of endometriosis [x].

Pueraria lobata 

Research has found that Pueraria flower extract (PFE) can reduce MMP-2 and MMP-9 mRNA and protein levels in endometriotic cells and suppress their adhesion and migration. These findings suggest that Pueraria lobata might have therapeutic potential in managing endometriosis by affecting the behavior of endometriotic cells [x].

Hexane extract of Aged Black Garlic

The research on aged black garlic, specifically its hexane extract (HEABG), highlights significant potential in the treatment and management of endometriosis. Key findings from studies have shown that HEABG can inhibit cell proliferation and cell cycle progression in tumor necrosis factor (TNF)-α-activated human endometriotic stromal cells. This effect is mediated by inhibiting the ERK and JNK signaling pathways [x].

Furthermore, HEABG’s impact on TNF-α-induced expression of intercellular adhesion molecule (ICAM)-1 and vascular adhesion molecule (VCAM)-1 has been observed. This effect is achieved by inhibiting the activation of nuclear factor-kappa B (NF-κB) and nuclear activator protein-1 transcription factors [x].

These mechanisms are crucial because they may impede the recruitment of immune cells into endometriotic lesions, thereby potentially reducing disease-associated inflammation.  These findings position aged black garlic, particularly its hexane extract, as a promising candidate for further research in endometriosis treatment. The antioxidant, anti-cancer, and pro-apoptotic properties of aged black garlic extracts have been noted in various studies, contributing to a growing body of evidence supporting its therapeutic potential in a range of pathologies [x].

Resveratrol

The potential therapeutic effects and molecular mechanisms of resveratrol on endometriosis are primarily due to its anti-inflammatory, anti-proliferative, anti-angiogenic, and antioxidative properties [x].

Several studies have demonstrated that resveratrol can inhibit the growth and angiogenesis (formation of new blood vessels) of endometrial tissue, which is a key factor in the development of endometriosis. It has been observed that resveratrol supplementation in animal models of endometriosis resulted in a decrease in the number and volume of endometrial implants, as well as a suppression of proliferation, vascularization, and inflammation in these implants [x] .

Furthermore, resveratrol has been shown to increase apoptosis (programmed cell death) in endometriotic cells and reduce their invasiveness. This suggests that resveratrol could potentially alter the cellular mechanisms that drive the progression of endometriosis. [x, x].
Catechins (green tea)
Catechins, particularly epigallocatechin-3-gallate (EGCG) found in green tea, have shown promising effects in the context of endometriosis. Research indicates that EGCG has several biological properties, such as anti-angiogenic, anti-proliferation, anti-metastasis, and apoptosis induction, which can be beneficial in the management of endometriosis.

One of the key mechanisms through which EGCG may improve endometriosis is its anti-angiogenic properties. The development of new blood vessels is crucial for the growth and survival of endometriosis, and EGCG has been found to significantly inhibit this process. In experimental models, EGCG treatment led to smaller endometriotic lesions, reduced angiogenesis in the lesions, and down-regulation of angiogenic factors such as vascular endothelial growth factor A. Additionally, EGCG induced more apoptosis in the lesions and up-regulated certain genes involved in inflammatory responses.


These findings suggest that catechins like EGCG could be a valuable addition to the therapeutic options for endometriosis, potentially addressing aspects like inflammation, oxidative stress, invasion, adhesion, and angiogenesis associated with the condition. However, it’s important to note that while these preclinical studies are promising, further research, including clinical trials, is needed to fully establish the efficacy and safety of catechins in the treatment of endometriosis in humans [x , x.

Curcumin

Curcumin, a principal polyphenol isolated from turmeric, has shown potential therapeutic effects in the treatment of endometriosis. Research indicates that curcumin’s beneficial impact on endometriosis may be due to its anti-inflammatory, antioxidant, anti-tumor, anti-angiogenesis, and anti-metastatic activities [x].


One study focused on the inhibitory effect of curcumin on human endometriosis endometrial cells. The findings suggest that curcumin can decrease the growth of human ectopic and eutopic stromal cells associated with endometriosis. Specifically, treatment with curcumin led to an increase in the percentage of G1-phase cells and a decrease in S-phase cells, particularly at a concentration of 50 µmol/l. This indicates a potential for curcumin to inhibit cell proliferation. Furthermore, the study found that curcumin treatment decreased the expression of Vascular Endothelial Growth Factor (VEGF), suggesting that curcumin may mediate its effects through the downregulation of the VEGF signaling pathway, which is crucial for cell survival in endometriotic stromal cells [x] .

These findings provide evidence that curcumin may have therapeutic potential in endometriosis by affecting cell proliferation and survival, possibly through mechanisms involving the modulation of key signaling pathways like VEGF.

Uncaria tomentosa

↓ Endometriotic lesion size [x].

Açai extract

↓ Endometriotic lesion size
↓ VEGF, MMP-9 and COX-2
↓ PGE2, VEGF and NO levels
[x

Viburnum opulus

↓ Endometriotic lesion size
↓ TNF-α, VEGF and IL-6 levels
[x]

Milk thistle (Silybum marianum)

↓ Endometriotic lesion size [x]
↑ ERK1/2 expression
↓ Angiogenesis
↑ Apoptosis
↑ Fibrosis

[x]

Calligonum comosum

↓ Endometriotic lesion size
↓ Vascularisation
↓ Cell proliferation
↓ Immune cell infiltration


[x.

Probiotics

Probiotics and prebiotics have shown potential in optimizing, maintaining, and restoring vaginal microflora, offering alternative approaches to reduce vaginal infections and promote overall female health. [x]

Melatonin

[x]

Vitamin D
[x, x, x]

NAC (N-Acetylcysteine) 

Oral supplementation with NAC improves endometriosis-related pain, and appears to improve fertility in patients with endometriosis [x].

Frankincense (Boswellia serrata)

Frankincense ameliorates endometriosis via inducing apoptosis and reducing adhesion [x].

Frankincense oils have also demonstrated synergistic, additive, and non-interactive properties against various microorganisms. Particularly, Cryptococcus neoformans and Pseudomonas aeruginosa were found to be most susceptible to these oils [x].
Vitamin B1 (Thiamine)Vitamin B1 (Thiamine) has been shown to reduce the symptoms of endometriosis [x]. Vitamin B1 is essential for energy metabolism and neural function. Its anti-inflammatory properties could potentially alleviate pain and other symptoms associated with endometriosis [x, x].

Potentially Effective Supplements

The likelihood of many other effective but unstudied treatment options for endometriosis is significant, primarily due to the complexity of the condition and the evolving understanding of its pathophysiology. Endometriosis is a multifaceted disease with diverse manifestations, and research continually uncovers new aspects of its etiology and progression. This ongoing research frequently leads to the identification of potential new treatment targets. However, the development and validation of these treatments require extensive clinical trials and studies, which means many potentially effective therapies remain unexplored or in the early stages of investigation. Additionally, the individual variation in disease presentation and response to treatments further supports the notion that there may be numerous untapped strategies for managing endometriosis effectively.


Utilizing microbiome signatures to explore treatment options for endometriosis involves understanding the unique microbial profiles associated with the condition. These signatures can reveal insights into the disease’s pathophysiology, potentially highlighting specific microbial imbalances or interactions that contribute to endometriosis. By identifying these unique microbial patterns, researchers can develop targeted therapies aimed at restoring a healthy microbiome balance. This approach could lead to more personalized treatments, focusing on modulating the microbiome to alleviate symptoms or even addressing underlying causes of endometriosis.


Celyon Cinnamon Oil 
While Ceylon cinnamon may be used in traditional or alternative treatments for endometriosis, its effectiveness has not been confirmed in clinical trials​. Nonetheless, Ceylon cinnamon oil does have activity against pathogens consistent with the Microbiome Signature of Endometriosis.

Cinnamomum zeylanicum (CZ-EO) essential oil showed moderate activity against Fusobacterium nucleatum and Streptococcus mutans. The minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) for Fusobacterium nucleatum were both found to be 125 μg/mL, while for Streptococcus mutans, the MIC was 200 μg/mL and the MBC was 400 μg/mL [x] .

Asparagus racemosus

Asparagus racemosus has demonstrated considerable antibacterial efficacy against various pathogenic bacteria. In a study, different concentrations of the methanol extract of Asparagus racemosus roots were tested and found to be effective against a range of bacteria implicated in the pathogenesis of endometriosis, including Escherichia coli, Shigella dysenteriae, Shigella sonnei, Shigella flexneri, Vibrio cholerae, Salmonella typhi, Salmonella typhimurium, Pseudomonas putida, Bacillus subtilis, and Staphylococcus aureus. [x.
D-Chiro InositolD-Chiro Inositol’s ability to reduce the development of endometriotic lesions in a mouse model suggests a therapeutic potential for this compound in the treatment of endometriosis. This finding is noteworthy because it opens a new avenue for non-hormonal treatment options, which can be particularly beneficial for patients who are unable to use hormonal therapies due to side effects or other contraindications [x].

Pharmacological Therapies for Endometriosis

The first-line treatment for endometriosis typically involves pain management and hormonal therapies. Pain relief is often addressed with nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen. Hormonal treatments, aimed at controlling the hormonal changes that contribute to endometriosis, may include hormonal contraceptives (like birth control pills, patches, or vaginal rings) and gonadotropin-releasing hormone (GnRH) agonists. These treatments help to reduce or eliminate menstrual periods, thereby alleviating the symptoms of endometriosis. The choice of treatment depends on the severity of symptoms, the woman’s age, and her plans for pregnancy. 

The biggest issue with first-line treatments for endometriosis, such as hormonal therapies and pain relievers, is that they often do not address the underlying cause of the condition. These treatments focus on symptom management rather than curing the disease. Hormonal treatments can have side effects and may not be suitable for women trying to conceive. Regarding vaginal dysbiosis, first-line treatments for endometriosis do not directly address it, as endometriosis primarily involves endometrial tissue growth outside the uterus and is not directly linked to the vaginal microbiome. 

However, some pharmacological targets may improve the vaginal microbiome, thereby directly influencing some of the factors involved in the pathophysiology of the disease. 

Oral ContraceptivesFor decades, estrogen-progestin oral contraceptive pills (OCPs) have been the standard first-line treatment for menstrual and pelvic pain associated with endometriosis, despite lacking solid clinical evidence for their effectiveness. While OCPs may offer initial relief, possibly by improving symptoms of primary dysmenorrhea, concerns have been raised about their long-term impact on the progression of endometriosis.

In contrast, evidence from randomized controlled trials supports oral progestin-only treatments, such as norethindrone acetate and dienogest, for managing pelvic pain and limiting the spread of endometriotic lesions, suggesting they may be preferable to OCPs for first-line therapy [x]. This perspective challenges the current guidelines from leading gynecologic societies, which recommend OCPs as the initial treatment for endometriosis-associated pain, despite only one randomized trial supporting OCP efficacy for dysmenorrhea in endometriosis patients, with no evidence of benefit for non-menstrual pelvic pain or dyspareunia.

Axitinib, Afatinib, Linifanib

Axitinib, Afatinib, and Linifanib, are known for their anti-angiogenic properties. Anti-angiogenesis refers to the process of inhibiting the growth of new blood vessels. In the context of endometriosis, this approach is relevant because the proliferation of blood vessels can support the growth and maintenance of endometrial tissue outside the uterus, a characteristic feature of endometriosis. By inhibiting these processes, these compounds could potentially reduce the growth and spread of endometrial tissue, thereby alleviating the symptoms of endometriosis.

The use of vaginal suppositories for direct drug delivery is also noteworthy, as it represents a targeted approach that might offer advantages over systemic treatments [x] .

3D-printed semisolid vaginal ovules containing pirfenidone

Pirfenidone, traditionally used for treating idiopathic pulmonary fibrosis, has been repurposed as a potential treatment for endometriosis. A study highlighted the development of 3D printed semisolid vaginal ovules containing pirfenidone for this purpose. This method allows for direct targeting of the reproductive organs and demonstrates improved efficacy and reduced side effects. The study showed that these mucoadhesive ovules have a controlled release profile of pirfenidone and better adhesion properties, making them a promising approach for endometriosis treatment​ [x].

Metronidazole
Metronidazole is a nitroimidazole antibiotic that is used to treat a wide array of protozoans and anaerobic bacteria [x].

Antibiotics have been explored as a potential therapy for endometriosis, particularly focusing on their effects on the gut microbiome. An animal study published in the journal Human Reproduction found that antibiotic therapy, specifically with metronidazole, reduced the progression of endometriosis. This effect was attributed to changes in the gut bacteria [x].

In the study, mice treated with broad-spectrum antibiotics, including vancomycin, neomycin, metronidazole, and ampicillin, showed significantly smaller endometriotic lesions compared to those treated with a vehicle. The treatment also reduced inflammatory responses. Interestingly, only metronidazole, but not neomycin, led to a significant reduction in the volume of ectopic lesions compared to vehicle-treated mice. This suggests a specific role for certain gut bacteria in the progression of endometriosis.

Of note, oral gavage of feces from mice with endometriosis restored the growth and inflammation of endometriotic lesions in metronidazole-treated mice, indicating a significant link between the gut microbiota and the disease​​​​​​.

Non-Pharmacological Interventions


Transvaginal Photobiomodulation 

Transvaginal reduced inflammation and improved pain in endometriosis study participants [x]
Vaginal Microbiome Transplant (VMT)
Vaginal microbiome transplantation (VMT) is an emerging therapeutic approach that mirrors the concept of fecal microbiome transplantation (FMT) but is focused on restoring the vaginal microbial balance. VMT involves transferring vaginal fluid from healthy donors to recipients who are experiencing issues like recurrent bacterial vaginosis (BV).

Comparing VMT to FMT, both aim to introduce a complete microbial community, rather than isolated bacterial species like traditional probiotics. This holistic approach is intended to help reestablish a healthy microbiome within the vagina, similar to how FMT restores gut microbiota in cases of recurrent C. difficile infections.

An animal model study investigating the efficacy of antibiotics and VMT for endometriosis found that both modalities were effective, and reduced disease progression via the NF-κB Signaling Pathway [x].

Fecal Transplant 

Recently, studies have shown that FMT can be used to treat female reproductive tract diseases [x,x]. Due to the role of gut microbiota in the development of endometriosis, FMT could be an innovative treatment option for the treatment of endometriosis.

Local pH Modification with lactic acid suppositories

Studies have found a significant shift in intra-vaginal pH to ≥4.5 in women with endometriosis compared to control women (79.3% versus 58.4%, P < 0.03). This suggests that women with endometriosis tend to have a higher vaginal pH compared to healthy controls​​ [x].

E. coli and Lactobacillus thrive in different pH environments. E. coli, a bacterium typically found in the intestines, prefers a neutral pH around 7. In contrast, Lactobacillus species, which are common in the vagina, thrive in acidic environments and help maintain a vaginal pH of around 3.5 to 4.5. This acidic environment is crucial for inhibiting the growth of harmful bacteria, including E. coli, and maintaining vaginal health. The acidic pH is primarily due to lactic acid produced by Lactobacillus.

Although local lactic acid has been demonstrated to exert beneficial effects through its capacity to destroy vaginal biofilms and restore vaginal microbiota in bacterial vaginosis (BV) without causing systemic effects, the use of lactic acid in the prophylaxis or treatment of BV is currently not included in treatment guidelines, and lactic acid has not been investigated for a potential microbiome-targeted therapy for endometriosis. 

Nonetheless, a positive change in the vaginal microbiota was demonstrated starting from 2 days after treatment initiation with lactic acid in pregnant women with symptomatic BV. After 1 week, 80% of the treated women were declared cured with the presence of a normal concentration of lactobacilli in the vaginal microbiota [x], indicating a potential treatment option for endometriosis.

Oral Sex 
Research suggests that women who reported engaging in oral sex were less likely to have endometritis, a condition associated with Pelvic Inflammatory Disease (PID). Although endometritis is distinctly different from endometriosis, the study proposes that oral sex could stimulate an effective immune response in the genital tract, possibly due to antigenic priming of the lymphatic system, which is abundant in the oropharynx. This hypothesis, however, requires further investigation for validation [x].
Tampons, Sexual activity, and orgasm during menstruationTampon use, sexual activity during menstruation, and orgasm might have a protective effect against endometriosis [x]. The study revealed that these behaviors were less frequent among women with endometriosis compared to controls, suggesting that engaging in these practices could potentially reduce the risk of developing the condition. This conclusion challenges the initial hypothesis that these factors would increase the risk of endometriosis through mechanisms such as retrograde menstruation.

The potential protective effect might be explained by mechanisms such as improved menstrual fluid clearance and facilitation of cervical outflow, which could counteract the process of retrograde menstruation believed to contribute to the development of endometriosis. However, these findings are preliminary and were unexpected, highlighting the need for further research to understand the underlying mechanisms and to verify the protective role of these practices against endometriosis more definitively.


Cotton undergarments 

While the importance of breathable fabrics like cotton for maintaining vaginal health is often highlighted in health advice and articles, there is a gap in clinical research directly linking the type of underwear fabric to specific reproductive health outcomes. This suggests an area for future research to provide more evidence-based guidance on this topic.

Nonetheless, there is interaction between different types of bacteria and various fabric materials. Studies have shown that bacteria implicated in the etiology of endometriosis, specifically Staphylococcus aureus and Staphylococcus epidermidis, demonstrated increased adherence to fabrics as the content of polyester fibers in the fabrics increased [x].

Understanding these dynamics is crucial, particularly in relation to female reproductive health and infection control. The findings highlight that the material composition of fabrics can influence bacterial adherence, which could have implications for infection prevention strategies.
Iron Chelation TherapyExcess iron can lead to toxicity and be associated with pathological disorders. In the context of endometriosis, research has demonstrated iron overload in different components of the peritoneal cavity, including peritoneal fluid, endometriotic lesions, peritoneum, and macrophages.

The cumulative effect of iron overload on these cell types may contribute to the development and progression of endometriosis. Iron-induced inflammation and oxidative stress are potential mechanisms through which iron overload can influence the pathophysiology of the disease.

Iron chelator treatment as a potential therapeutic approach in endometriosis has been explored in research.
Pro-apoptotic peptidesCombining a targeted peptide (z13) with a pro-apoptotic peptide (dKLAK) and an endosome-escaping peptide (HLAH) induced apoptosis in endometriosis cells in baboon models offers a potential therapeutic strategy [x].

The use of phage display technology facilitated the identification of z13, which binds specifically to CNGB3, a protein highly expressed in endometrial glandular epithelial cells. This targeting is significant for addressing endometriosis, as it can reach cells on peritoneal surfaces, challenging to remove surgically.

Despite promising in vitro results, the in vivo efficacy of z13 was modest, possibly due to the peritoneal environment’s influence, suggesting the need for controlled-release formulations to improve outcomes. Future research should explore targeting both epithelial and stromal cells within endometriosis lesions for a more comprehensive treatment approach, indicating a promising, yet initial, step towards novel endometriosis therapeutics.

Custom phage cocktails Combining a targeted peptide (z13) with a pro-apoptotic peptide (dKLAK) and an endosome-escaping peptide (HLAH) induced apoptosis in endometriosis cells in baboon models offers a potential therapeutic strategy [x].

The use of phage display technology facilitated the identification of z13, which binds specifically to CNGB3, a protein highly expressed in endometrial glandular epithelial cells. This targeting is significant for addressing endometriosis, as it can reach cells on peritoneal surfaces, which are challenging to remove surgically.

Despite promising in vitro results, the in vivo efficacy of z13 was modest, possibly due to the peritoneal environment’s influence, suggesting the need for controlled-release formulations to improve outcomes. Future research should explore targeting both epithelial and stromal cells within endometriosis lesions for a more comprehensive treatment approach, indicating a promising, yet initial, step towards novel endometriosis therapeutics.

Diagnosis

Estimating the prevalence of endometriosis is challenging due to asymptomatic cases and diagnostic delays, averaging about ten years. The disease’s prevalence is roughly 5%, peaking between ages 25 and 35, and often regresses after menopause. Endometriosis manifests in peritoneal or superficial endometriosis, ovarian endometrioma (OMA), or deep infiltrating endometriosis (DIE). Common symptoms include chronic pelvic pain, dysmenorrhea, and urinary or bowel issues. Diagnosis involves physical exams, ultrasonography, MRI, and, traditionally, laparoscopy. CA125 is a serum marker used in diagnosis but with serious limitations. Fortunately, recent research focusing on non-invasive diagnostic tools has emerged.

Using the Metabolomic Signature for the Diagnosis of Endometriosis 

Endometriosis is marked by increased protein turnover, leading to elevated blood amino acid levels in response to catabolic damage. Metabolite studies in patients’ serum aid in diagnosis. For instance, lower levels of certain amino acids like alanine, lysine, phenylalanine, and leucine in endometrial tissue contrast with their higher serum levels. These variations in amino acid levels offer potential diagnostic markers for endometriosis. Additionally, the chronic inflammatory nature of endometriosis affects energy metabolism, with altered levels of glutamine and glutamate observed in affected tissues, providing potential non-invasive diagnostic opportunities.


Biomarkers

Serum Concentrations

Amino Acids

⬆ Alanine
⬆ Lysine
⬆ Phenylalanine
⬆ Leucine
⬆ Valine
⬆ Threonine
⬆ Taurine
⬇ Arginine
⬇ Leucine
[x, x

Lipids

⬆ Sphyngomielins
⬆ Ether-phospholipids
[x]

Sugars

⬇ Glucose [x]

Organic Acids

⬆ Lactate  
⬆ 2-Hydroxybutyrate 
⬆ 3-Hydroxybutyrate 
[x]

Other metabolites

⬆ 2-Methoxyestradiol
⬆ 2-Methoxyestrone
⬆ Dehydroepiandrosterone
⬆ Androstenedione
⬆ Cholesterol
⬇ Primitive bile acids [x]
⬆ Acyl-carnitine (long-chain) [x]


Sample Tissue
Biomarkers

Endometrial tissue 

⬇ Alanine
⬇ Lysine
⬇ Phenylalanine
⬇ Leucine
[x]

Endometriotic Tissue

⬇ Formate
[x]

Endometrial fluid

⬇ Monohexosylceramides
⬇⬆Ceramides
⬆Glycerophospholipids 
⬆Glycerolipids 
[x]

Follicular fluid

⬆Phosphatidylcholines 
[x]

Adipose and Peripheral tissue

⬆ Estradiol 
[x]

Cerebral tissue

⬆ Glutamine 
[x]

Urine

⬆ Taurine
⬆ Valine
⬆ Guanidino-succinate
⬆ Creatinine
⬆ 2-Hydroxyisovalerate
[x]

Endometriosis-Associated Risks

Individuals with endometriosis may be at an increased risk for certain comorbidities and associated conditions. While endometriosis primarily affects the tissue lining the uterus (endometrium), it can have systemic effects and influence various aspects of a person’s health. Some of the conditions and health risks that individuals with endometriosis may be more prone to include:

Associated Risks
Pelvic Pain and DiscomfortEndometriosis is known for causing chronic pelvic pain, which can significantly impact a person’s quality of life.
InfertilityEndometriosis can lead to the formation of adhesions and scar tissue in the pelvic area, which may interfere with reproductive organs and fertility.
Ovarian CystsEndometriomas, also known as “chocolate cysts,” are cysts that can form on the ovaries in individuals with endometriosis.
AdenomyosisThis condition involves the growth of endometrial tissue within the muscular wall of the uterus, leading to painful and heavy menstrual bleeding.
DysmenorrheaEndometriosis is a common cause of severe menstrual cramps (dysmenorrhea).
Chronic FatigueChronic pain and other symptoms of endometriosis can contribute to fatigue and reduced energy levels.
Irritable Bowel Syndrome (IBS)Some individuals with endometriosis may experience gastrointestinal symptoms resembling IBS, such as bloating, diarrhea, or constipation.
Interstitial CystitisThis painful condition affecting the bladder can sometimes coexist with endometriosis.
FibromyalgiaThere may be an association between endometriosis and fibromyalgia, a condition characterized by widespread pain and sensitivity.
Depression and AnxietyChronic pain and the emotional toll of dealing with a chronic condition like endometriosis can contribute to mental health challenges.
Autoimmune DiseasesSome studies have suggested a potential link between endometriosis and certain autoimmune disorders.
Ovarian CancerThe chronic inflammation hypothesis suggests that the persistent inflammation associated with endometriosis may create a favorable microenvironment for the initiation and progression of ovarian cancer. This inflammatory milieu may lead to DNA damage, genetic mutations, and the promotion of abnormal cell growth, which are carcinogenic factors.

The Chronic Inflammation Model of Carcinogenesis

The chronic inflammation model of carcinogenesis posits that sustained exposure to external or internal factors that activate the immune system, along with the presence of persistent immune cells, can lead to damage to the surrounding epithelial cells. This damage may occur through various mechanisms, including releasing reactive oxygen species (ROS) or producing cytokines that stimulate cell proliferation.

In this model, chronic inflammation plays a pivotal role in initiating and promoting the development of cancer. The continuous activation of the immune system can create a microenvironment within the affected tissue that is conducive to the accumulation of genetic mutations and DNA damage. ROS, which are highly reactive molecules, can directly harm DNA, leading to genetic alterations that can drive carcinogenesis.

Furthermore, the pro-inflammatory cytokines produced by immune cells can stimulate the proliferation of damaged or mutated cells, thereby contributing to the expansion of abnormal cell populations. Over time, these changes can increase the likelihood of oncogenic events and the progression towards cancer.

It is important to note that the chronic inflammation model highlights the intricate interplay between the immune system, tissue damage, and genomic instability in the context of cancer development. Understanding these mechanisms is crucial for designing targeted therapeutic interventions and preventive strategies aimed at reducing cancer risk associated with chronic inflammatory conditions.

Ovarian Cancer

Several epidemiological studies have indeed found an association between a history of endometriosis and an increased risk of certain types of invasive epithelial ovarian cancers.

A pooled analysis of 13 case-control studies demonstrated that a history of endometriosis was associated with an elevated risk of clear cell, low-grade serous, and endometrioid invasive ovarian cancers. However, this increased risk was not observed for mucinous or high-grade serous ovarian cancers. This variation in risk among different ovarian cancer subtypes suggests that there may be distinct mechanisms at play.

Endometriosis is considered a pelvic inflammatory condition. While its exact causes still remain unclear, some research suggests that inflammatory substances, including poly-halogenated aromatic hydrocarbons and xenoestrogens may also trigger it. These substances could potentially induce toxic inflammation in the pelvic region, contributing to the development of endometriosis.

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