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Endometriosis is a chronic inflammatory disease causing distressing symptoms and requiring a life-long management strategy. The objective of this review is to evaluate endometriosis-related pathways and identify novel therapies to treat it. We focused on the crucial role of inflammation and inflammatory molecules in order to define new perspectives for non-hormonal treatment of the disease by targeting inflammation, nuclear factor kappa B and cytokines, or reactive oxygen species, apoptotic and autophagic pathways, regulators of epithelial-mesenchymal transition, and angiogenesis and neuroangiogenesis. Novel non-steroidal therapies targeting these pathways for endometriosis were explored, but multiple challenges remain. While numerous agents have been investigated in preclinical trials, few have reached the clinical testing stage because of use of inappropriate animal models, with no proper study design or reporting of preclinical strategies. Targeting estrogens is still the best way to control endometriosis progression and inflammation.

Endometriosis is a female reproductive disorder characterized by growth of uterine cells and tissue in distant sites. Around 2-10% of women experience this condition during reproductive age, 35-50% of whom encounter fertility issues or pain. To date, there are no established methods for its early diagnosis and treatment, other than surgical procedures and scans. It is difficult to identify the disease at its onset, unless symptoms such as infertility and/or pain are present. Determining the mechanisms involved in its pathogenesis is vital, not only to pave the way for early identification, but also for disease management and development of less invasive but successful treatment strategies. Endometriosis is characterized by cell proliferation, propagation, evasion of immunosurveillance, and invasive metastasis. This review reports the underlying mechanisms that are individually or collectively responsible for disease establishment and evolution. Treatment of endometriosis mainly involves hormone therapies, which may be undesirable or have their own repercussions. It is therefore important to devise alternative strategies that are both effective and cause fewer side effects. Use of phytochemicals may be one of them. This review focuses on pharmacological inhibitors that can be therapeutically investigated in terms of their effects on signaling pathways and/or mechanisms involved in the pathogenesis of endometriosis.

To evaluate the effectiveness of a new class of medical drugs, namely oral gonadotropin-releasing hormone (GnRH) antagonists, in the management of premenopausal women with endometriosis-associated pelvic pain. We reviewed the most relevant papers ( n = 27) on the efficacy of new medical alternatives (oral GnRH antagonists) as therapy for endometriosis. We first briefly summarized the concept of progesterone resistance and established that oral contraceptives and progestogens work well in two-thirds of women suffering from endometriosis. Since clinical evidence shows that estrogens play a critical role in the pathogenesis of the disease, lowering their levels with oral GnRH antagonists may well prove effective, especially in women who fail to respond to progestogens. There is a need for reliable long-term oral treatment capable of managing endometriosis symptoms, taking into consideration both the main symptoms and phenotype of the disease. Published studies reviewed and discussed here confirm the efficacy of GnRH antagonists. There is a place for GnRH antagonists in the management of symptomatic endometriosis. Novel algorithms that take into account the different phenotypes are proposed.

Uterine adenomyosis is a common chronic disorder frequently encountered in reproductive-age women, causing heavy menstrual bleeding, intense pelvic pain, and infertility. Despite its high prevalence, its etiopathogenesis is not yet fully understood, so there are currently no specific drugs to treat the disease. A number of dysregulated mechanisms are believed to contribute to adenomyosis development and symptoms, including sex steroid signaling, endometrial proliferation and invasiveness, and aberrant immune response. Abnormal sex steroid signaling, particularly hyperestrogenism and subsequent progesterone resistance, are known to play a pivotal role in its pathogenesis, which is why various antiestrogenic agents have been used to manage adenomyosis-related symptoms. Among them, gonadotropin-releasing hormone (GnRH) antagonists are swiftly gaining ground, with recent studies reporting efficient lesion regression and symptom alleviation. The aim of the present review is to compile available information on the pathogenesis of adenomyosis, explore the etiology and mechanisms of hyperestrogenism, and discuss the potential of antiestrogenic therapies for treating the disease and improving patient quality of life.

Endometriosis is a disease of reproductive age characterized by chronic pelvic pain and infertility. Its pathogenesis is complex and still partially unexplained. However, there is increasing evidence of the role of chronic inflammation, immune system dysregulation, and oxidative stress in its development and progression. The latter appears to be involved in multiple aspects of the disease. Indeed, disease progression sustained by a hyperproliferative phenotype can be related to reactive oxygen species (ROS) imbalance, as numerous experiments using drugs to counteract hyperproliferation have shown in recent years. Chronic pelvic pain is also associated with cell function dysregulation favoring chronic inflammation and oxidative stress, specifically involving macrophages and mast cell activation. Moreover, there is increasing evidence of a role for ROS and impaired mitochondrial function not only as deleterious effectors of the ovarian reserve in patients with endometriomas but also in terms of oocyte quality and, hence, embryo development impairment. Targeting oxidative stress looks to be a promising strategy to both curb endometriotic lesion progression and alleviate endometriosis-associated symptoms of chronic pain and infertility. More investigations are nevertheless needed to develop effective therapeutic strategies for clinical application.

Currently, the extracellular matrix (ECM) is considered a pivotal complex meshwork of macromolecules playing a plethora of biomolecular functions in health and disease beyond its commonly known mechanical role. Only by unraveling its composition can we leverage related tissue engineering and pharmacological efforts. Nevertheless, its unbiased proteomic identification still encounters some limitations mainly due to partial ECM enrichment by precipitation, sequential fractionation using unfriendly-mass spectrometry (MS) detergents, and resuspension with harsh reagents that need to be entirely removed prior to analysis. These methods can be technically challenging and labor-intensive, which affects the reproducibility of ECM identification and induces protein loss. Here, we present a simple new method applicable to tissue fragments of 10 mg and more. The technique has been validated on human ovarian tissue and involves a standardized procedure for sample processing with an MS-compatible detergent and combined centrifugation. This two-step protocol eliminates the need for laborious sample clarification and divides our samples into 2 fractions, soluble and insoluble, successively enriched with matrisome-associated (ECM-interacting) and core matrisome (structural ECM) proteins.