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Establishment of an Experimental Mouse Model of Endometrioma to Study its Related Infertility

Endometrioma (OMA), a subtype of endometriosis characterized by the formation of endometriotic cysts in the ovaries, affects 17-44% of individuals ...

The Chinese University of Hong Kong

Endometriosis (EM) is defined as endometrial tissues found outside the uterus. Growth and development of endometriotic cells in ectopic sites can be promoted via multiple pathways, including MAPK/MEK/ERK, PI3K/Akt/mTOR, NF-κB, Rho/ROCK, reactive oxidative stress, tumor necrosis factor, transforming growth factor-β, Wnt/β-catenin, vascular endothelial growth factor, estrogen, and cytokines. The underlying pathophysiological mechanisms include proliferation, apoptosis, autophagy, migration, invasion, fibrosis, angiogenesis, oxidative stress, inflammation, and immune escape. Current medical treatments for EM are mainly hormonal and symptomatic, and thus the development of new, effective, and safe pharmaceuticals targeting specific molecular and signaling pathways is needed. Here, we systematically reviewed the literature focused on pharmaceuticals that specifically target the molecular and signaling pathways involved in the pathophysiology of EM. Potential drug targets, their upstream and downstream molecules with key aberrant signaling, and the regulatory mechanisms promoting the growth and development of endometriotic cells and tissues were discussed. Hormonal pharmaceuticals, including melatonin, exerts proapoptotic via regulating matrix metallopeptidase activity while nonhormonal pharmaceutical sorafenib exerts antiproliferative effect via MAPK/ERK pathway and antiangiogenesis activity via VEGF/VEGFR pathway. N-acetyl cysteine, curcumin, and ginsenoside exert antioxidant and anti-inflammatory effects via radical scavenging activity. Natural products have high efficacy with minimal side effects; for example, resveratrol and epigallocatechin gallate have multiple targets and provide synergistic efficacy to resolve the complexity of the pathophysiology of EM, showing promising efficacy in treating EM. Although new medical treatments are currently being developed, more detailed pharmacological studies and large sample size clinical trials are needed to confirm the efficacy and safety of these treatments in the near future.

Pharmaceuticals targeting signaling pathways of endometriosis as potential new medical treatment: A review.

Endometriosis is defined as endometrial tissues found outside the uterine cavity. ProEGCG is a prodrug of Epigallocatechin gallate (EGCG), a potent polyphenol found in green tea. It inhibits the development of endometriotic lesions of mouse model , with higher efficacy and more remarkable anti-oxidative ability than EGCG. Our study aims to identify the molecular binding targets and pharmacological actions of ProEGCG in treating endometriosis. Protein target interaction study is essential to fully characterize the mechanism of actions, related therapeutic effects, and side effects. We employed a combined approach, starting with an  reverse screening of protein targets and molecular docking, followed by  cellular thermal shift assay (CESTA) to assess the stability of protein-small molecule complexes. Then microarray and immunostaining of endometriotic lesions in mice  confirmed the molecular interaction of the selected targets after treatment. Our study identified enzymes nicotinamide nucleotide adenylyltransferase (NMNAT)1 and NMNAT3 as protein targets of ProEGCG  and  and were overexpressed after ProEGCG treatment . These findings suggested that participation in nicotinate and nicotinamide metabolism potentially regulated the redox status of endometriosis  its antioxidative capacities through binding to the potential therapeutic targets of ProEGCG.

An ,  and  Combined Approach to Identify NMNATs as Potential Protein Targets of ProEGCG for Treatment of Endometriosis.

Endometrioma (OMA) is the most common subtype of endometriosis, in which the endometriotic lesions are implanted in the ovary. Women with OMA are usually associated with infertility, presenting with reduced ovarian reserve, low oocyte quantity and quality, and poor fertility outcomes. However, the underlying pathological mechanisms in OMA-related infertility are still unclear. Due to the limitations and ethical issues of human studies in reproduction, animal models that recapitulate OMA characteristics and its related infertility are critical for mechanistic studies and subsequent drug development, preclinical testing, and clinical trials. This review summarized the investigations of OMA-related infertility based on previous and latest endometrioma models, providing the possible pathogenesis and potential therapeutic targets for further studies.

What We Have Learned from Animal Models to Understand the Etiology and Pathology of Endometrioma-Related Infertility.

Endometriosis is a common reproductive disorder characterized by the presence of endometrial implants outside of the uterus. It affects ~1 in 10 women of reproductive age. Endometriosis in the ovary, also known as endometrioma (OMA), is the most frequent implantation site and the leading cause of reproductive failure in affected women. Ovarian aging is one of the characteristic features of OMA, however its underlying mechanism yet to be determined. Accumulated evidence has shown that pelvic and local microenvironments in women with OMA are manifested, causing detrimental effects on ovarian development and functions. Whilst clinical associations of OMA with poor ovarian reserve, premature ovarian insufficiency, and early menopause have been reported. Moreover, surgical ablation, fenestration, and cystectomy of OMA can further damage the normal ovarian reservoir, and trigger hyperactivation of primordial follicles, subsequently resulting in the undesired deterioration of ovarian functions. Nevertheless, there is no effective treatment to delay or restore ovarian aging. This review comprehensively summarised the pathogenesis and study hypothesis of ovarian aging caused by OMA in order to propose potential therapeutic targets and interventions for future studies.

Impacts of endometrioma on ovarian aging from basic science to clinical management.

Endometriosis, a prevalent disorder in women of reproductive age, is often associated with undesired infertility. Ovarian reserve, an essential measure of ovarian function that is crucial for maintaining fecundity, is frequently diminished in women with endometriosis. Though the causative relationship between endometriosis and reduced ovarian reserve is not fully understood due to the lack of standardized and precise measurements of ovarian reserve, there is ongoing discussion regarding the impact of interventions for endometriosis on ovarian reserve. Therefore, in this review, we investigate articles that have related keywords and which were also published in recent years. Thereafter, we provide a comprehensive summary of evidence from in vitro, in vivo, and human studies, thereby shedding light on the decreased ovarian reserve in endometriosis. This research consolidates evidence from in vitro, in vivo, and human studies on the diminished ovarian reserve associated with endometriosis, as well as enhances our understanding of whether and how endometriosis, as well as its interventions, contribute to reductions in ovarian reserve. Furthermore, we explore potential strategies to modify existing therapy options that could help prevent diminished ovarian reserve in patients with endometriosis.

Diminished Ovarian Reserve in Endometriosis: Insights from In Vitro, In Vivo, and Human Studies-A Systematic Review.

Endometriosis is a common chronic gynecological disease with endometrial cell implantation outside the uterus. Angiogenesis is a major pathophysiology in endometriosis. Our previous studies have demonstrated that the prodrug of  gallate (ProEGCG) exhibits superior anti-endometriotic and anti-angiogenic effects compared to  gallate (EGCG). However, their direct binding targets and underlying mechanisms for the differential effects remain unknown. In this study, we demonstrated that oral ProEGCG can be effective in preventing and treating endometriosis. Additionally, 1D and 2D Proteome Integral Solubility Alteration assay-based chemical proteomics identified metadherin (MTDH) and PX domain containing serine/threonine kinase-like (PXK) as novel binding targets of EGCG and ProEGCG, respectively. Computational simulation and BioLayer interferometry were used to confirm their binding affinity. Our results showed that MTDH-EGCG inhibited protein kinase B (Akt)-mediated angiogenesis, while PXK-ProEGCG inhibited epidermal growth factor (EGF)-mediated angiogenesis via the EGF/hypoxia-inducible factor (HIF-1a)/vascular endothelial growth factor (VEGF) pathway.  and  knockdown assays and microvascular network imaging further confirmed the involvement of these signaling pathways. Moreover, our study demonstrated that ProEGCG has superior therapeutic effects than EGCG by targeting distinct signal transduction pathways and may act as a novel antiangiogenic therapy for endometriosis.

Article	Year
Pharmaceuticals targeting signaling pathways of endometriosis as potential new medical treatment: A review. Medicinal research reviews\| PubMed ID: 33948974	2021
An , and Combined Approach to Identify NMNATs as Potential Protein Targets of ProEGCG for Treatment of Endometriosis. Frontiers in pharmacology\| PubMed ID: 34721014	2021
What We Have Learned from Animal Models to Understand the Etiology and Pathology of Endometrioma-Related Infertility. Biomedicines\| PubMed ID: 35884788	2022
Impacts of endometrioma on ovarian aging from basic science to clinical management. Frontiers in endocrinology\| PubMed ID: 36686440	2022
Diminished Ovarian Reserve in Endometriosis: Insights from In Vitro, In Vivo, and Human Studies-A Systematic Review. International journal of molecular sciences\| PubMed ID: 37958954	2023
Distinct molecular targets of ProEGCG from EGCG and superior inhibition of angiogenesis signaling pathways for treatment of endometriosis. Journal of pharmaceutical analysis\| PubMed ID: 38352946	2024

Zhouyurong Tan

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