Polyphenols As A Diet Therapy Concept For Endometriosis—Current Opinion And Future Perspectives (Part 1)

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Abstract: Endometriosis represents an often painful, estrogen-dependent gynecological disorder, defined by the existence of endometrial glands and stroma exterior to the uterine cavity. The disease provides a wide range of symptoms and affects women's quality of life and reproductive functions. Despite research efforts and extensive investigations, this disease's pathogenesis and molecular basis remain unclear. Conventional endometriosis treatment implies surgical resection, hormonal therapies, and treatment with nonsteroidal anti-inflammatory drugs, but their efficacy is currently limited due to many side effects. Therefore, exploring complementary and alternative therapy strategies, minimizing the current treatments' adverse effects, is needed. Plants are sources of bioactive compounds that demonstrate broad-spectrum health-promoting effects and interact with molecular targets associated with endometriosis, such as cell proliferation, apoptosis, invasiveness, inflammation, oxidative stress, and angiogenesis. Anti-endometriotic properties are exhibited mainly by polyphenols, which can exert a potent phytoestrogen effect, modulating estrogen activity. The available evidence derived from preclinical research and several clinical studies indicates that natural biologically active compounds represent promising candidates for developing novel strategies in endometriosis management. The purpose of this review is to provide a comprehensive overview of polyphenols and their properties valuable for natural treatment strategy by interacting with different cellular and molecular targets involved in endometriosis progression.

Keywords: endometriosis; diet therapy; polyphenols; molecular targets; apoptosis; invasion; angiogenesis; inflammation; oxidative stress

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1. Introduction

Endometriosis is a chronic gynecological disorder, defined by the implantation of endometrial glands and stroma outside the uterine cavity, mainly in the pelvic peritoneum and ovaries. It affects approximately 10-15% of women of reproductive age, which extrapolates to around 190 million women worldwide [1,2]. Most affected patients often suffer from chronic pelvic pain, dyspareunia, dysmenorrhea, abnormal uterine bleeding, and infertility [3, A4]. All these symptoms provide an impact on a patient's quality of life, resulting in depression, anxiety, and impaired social function caused by the severity of pain [5]. The successful diagnosis of endometriosis requires surgical exploration or laparoscopy with histological confirmation [6l; therefore, the prevalence of the disease, its symptoms, associated disorders, and risk factors are limited data, only to the group of patients with definitive diagnosis [7].

Various hypotheses have been proposed to explain endometriosis pathology and tissue scattering throughout the abdominal cavity [8]. Distinct biological and clinical features indicate different types of endometriosis. Endometriosis can occur in several forms, according to histopathology and its anatomical localization in the pelvis: as the ovarian endometriotic cysts, deep infiltrating endometriosis, and superficial peritoneal lesions of varying colors [9]. Although scientists devoted significant effort to explaining pathogenesis and endometriosis-associated pain, the basics of many biological processes remain enigmatic. Despite multiple theories explaining endometriosis pathogenesis, every concept suggests that endometriosis is a complex multifactorial and heterogeneous disease of uncertain etiology; its development and progression are influenced by genetic, immunological, hormonal, and environmental factors [10]. Recently, Lagana et al. (2019) summarized existing theories and divided them into two main categories: transplantation and in situ [8]. Transplantation theory assumes that endometriosis develops due to eutopic endometrium metastasis to distinct sites by the hematogenous or lymphatic spread ]8,11. In contrast, in situ theory refers to endometriosis tissue existence caused by coelomic metaplasia, peritoneal mesothelium transformation into glandular endometrium, or embryologic origin [8]. A separate theory does not explain the different clinical presentations and pathological forms in endometriosis. The formation and persistence of endometriotic tissues at ectopic sites essentially depend on the fundamental biological process as adhesion, proliferation, cell invasion, local inflammation, immune dysregulation, and neoangiogenesis [2]. Another increasingly reported important hallmark in endometriosis's pathogenesis is the growth of new nerve fibers in endometriotic lesions, stimulated by inflammatory mediators and responsible for endometriosis-associated chronic pain conditions [12].

2. Current Treatment

Endometriosis therapy depends on the patient's predominant symptoms, such as age, side-effect profile, the extent and location of endometriotic lesions, and previous treatment [13]. The main therapeutic approach includes surgery, pharmacotherapy, and long-term comprehensive individual treatment [14,15]. Surgical intervention represents a primary treatment aimed at destroying or removing ectopic endometriotic lesions. Indeed, surgery generally increases pain relief in some but not all women. Although the surgical resection option completely removes all visible ectopic endometriotic lesions, high recurrence rates of up to 50% within five years of surgery are reported [16].

The most common pharmacological approach for endometriosis therapy is non-steroidal anti-inflammatory drugs for managing pain symptoms, combined with oral contraceptives [17,18]. Hormone therapy aims to induce hypoestrogenic, inhibition of tissue proliferation, and inflammation [19]. Second-line treatments that suppress systemic estrogen levels include progestin monotherapy and gonadotrophin-releasing hormone agonists (GnRH)[20]. The efficacy of conventional medical treatments is limited or intermittent in most patients. It brings a plethora of side effects like perimenopausal stage symptoms, osteoporosis, breakthrough bleeding, lipid profile changes, and liver dysfunction, resulting from the hypo-estrogenic state induced by this medical approach [21,22]. Consequently, exploring additional and alternative options is needed to improve treatment outcomes for patients with endometriosis. Strategies that complement conventional drug therapy may include non-pharmaceutical options: acupuncture, diet changes, supplementations, and phytotherapy [23-25]. Natural therapies constitute an option of paramount importance that can accelerate the healing process and help minimize the current treatment's adverse effects. The search for new alternative therapies should start with demonstrating their benefits and safety, evidence-based core outcomes obtained using endometriotic models [26].

3. Nutritional and Dietary Aspects of Endometriosis

Because of the unsuccessful treatment and chronic character of endometriosis, many women affected by endometriosis use additional management strategies to control this disease themselves [27]. According to the last Australian national online survey, as many as 76% of endometriosis women use non-pharmacological practices and lifestyle choices like relaxation techniques, movement, and nutrition. Almost half the women managed dietary support, and the diet's effectiveness had high self-reported improvement scores [28]. In recent years, an increasing number of endometriosis patients have focused on health-promoting and therapy-supporting dietary factors [29].

Plants are promising sources of bioactive compounds, potentially improving thera-peutic strategies [30]. Different pathways involved in the physiological and pathological processes associated with endometriosis, including altered inflammatory microenvironment, the attachment and invasion mechanisms, angiogenesis, estrogen activity, menstrual cyclicity, organochlorine burden, and prostaglandin metabolism, can be a target of food bioactive compounds [15,29,31]. Dietary treatment of endometriosis may be based on the estrogen dependency of endometriosis, and estrogen-lowering diet components may be used to treat or regress endometriosis [29,32]. Changing dietary patterns for endometriosis may help reduce inflammatory markers, shown to be increased in endometriosis [33]. The diet to treat endometriosis can moderate prostaglandins' effects responsible for the pain during endometriosis progression [34]. Different active compounds offering various therapeutic properties such as antiproliferative, anti-inflammatory, antioxidant, and analgesic properties are considered a complex group of molecular compounds effective in endometriosis [35].

There are many scientific studies on the effects of nutrition on endometriosis. Most papers have reported case-control studies evaluating the role of diet on endometriosis risk, while the diet effectiveness and diet compound potential in endometriosis treatment have been investigated less frequently. In our opinion, a scientific basis for the action of bioactive compounds in the management of endometriosis should be considered, and their possible curative effect described to explain their contribution to the healing process and impact on the control of severe endometriotic symptoms.

4. Molecular Targets in Endometriosis Dietary Management

Plants are sources of natural bioactive compounds that demonstrate broad-spectrum health-promoting effects and interact with molecular targets associated with endometriosis, such as cell proliferation and apoptosis, cell adhesion, invasiveness, inflammation, oxidative stress, and angiogenesis. The anti-endometriotic potential of nutraceuticals can also concern a potent phytoestrogen effect modulating estrogen activity. Dysregulated physiological processes related to endometriosis, contributing potential molecular targets for bioactive polyphenol compounds, are schematically presented in Figure 1.

4.1.Cell Survival and Apoptosis

The proliferation of endometrial cells is primarily controlled by interactions between sex steroids and their corresponding receptors. Endometriotic tissue's proliferative potential is significantly higher in the eutopic endometrium of women with endometriosis than in the endometrium of disease-free patients [36. The complex microenvironment consists of proinflammatory and endocrine mediators in surrounding endometriotic lesions, promoting endometriotic cells proliferation [37]. Ectopic endometriotic tissues are characterized by reported markedly higher levels of estrogen receptor beta (ERβ) compared with eutopic endometrial tissues and cells. ERβ plays a critical role in anti-apoptosis signaling and is responsible for a mechanism of evasion from endogenous immune surveillance for cell survival through inactivation of TNFα-induced apoptosis complex and I and the apoptosome. ERβ also activates the cytoplasmic inflammasome components, resulting in increasing interleukin 1β(IL-1β), enhancing adhesion and proliferation of endometrial cells. [38]. Furthermore, proliferation is enhanced by high levels of estrogen in the microenvironment of endometriotic lesions provided by locally increased expression of aromatase and decreased 17β-hydroxysteroid dehydrogenase(17β-HSD) type 2 in endometriotic implants [9].

Nuclear factor-kappa B (NF-kB), a pleiotropic transcription factor, also plays a critical role in developing endometriosis by protecting cells from apoptosis via activating anti-apoptotic genes and inducing the proliferation of the endometriotic cells [39]. Under normal conditions, endometrial cells from healthy women during menstruation do not survive in ectopic locations because cell turnover is regulated by apoptosis, avoiding cell dissemination and attachment. Endometrial tissue's impaired susceptibility to apoptosis

leads to increased invasiveness and the abnormal survival of endometrial cells in the peritoneum [40]. Different studies suggest that dysregulated expression of specific proteins associated with apoptosis, including B-cell lymphoma 2(BCL-2) protein family, B-cell lymphoma-extra large(BCL-XL) protein, BCL-2 associated X(BAX) protein, FAS/FASL system, cysteine-aspartic proteases (caspases), and survivin represent possible factors involving in apoptosis resistance in endometriotic cells [41-43]. Some studies have evaluated the effect of different bioactive food compounds on mechanisms regulating endometriotic cells proliferation and apoptosis, suggesting their therapeutic potential.

4.2. Cell Attachment and Infusion

The initial attachment of refluxed endometrial tissue fragments to the pelvic peritoneum is the principal of Sampson's retrograde theory of endometriosis origin |44]. Sub-peritoneal endometriotic lesion establishment requires remodeling of the extracellular matrix of the peritoneal mesothelium and invasion in their surrounding environment [45]. Menstrual effluent and morphological alterations can easily damage the intact mesothelium—a protective barrier against the implantation; the own adhesion site can also be created to implant regurgitated endometrial cells [46-48]. The adhesion of endometrium fragments to the peritoneum in women with endometriosis is enhanced by the overproduction of cellular adhesion molecules that facilitate intercellular binding and cellular attachments with the extracellular matrix; including CD44 transmembrane glycoprotein, cell adhesion molecules(CAM) such as integrins, cadherins, selectins, the immunoglobulin superfamily (Ig-CAM), and transmembrane-anchored proteoglycans like syndecans [49,50].

The progression of the invasion of adjacent tissues requires extracellular matrix degradation. The breakdown and remodeling of extracellular matrix thought to be mainly modulated by matrix metalloproteinases (MMP), especially MMP-1,2, 3,9, and 11 and their inhibitors (tissue inhibitors of metalloproteinases, TIMP) [51]. MMPs are the initial mediators of maintenance and survival of endometriotic lesions, mainly that their expression enhances significantly in endometriotic implants [52]. Different hormones, inflammatory cytokines, including 1L-6, lL-1, and growth factors, regulate MMPs, The primary inhibitor is progesterone, which might indirectly regulate MMP expression through the plasminogen activator pathway, increasing the levels of plasminogen activator inhibitor 1 (PAI-1)and reducing the activation of latent MMP-proenzyme by plasmin [53].

4.3.Angiogenesis

The formation of new blood vessels is fundamental to creating and maintaining endometriotic lesions, especially in the peritoneal microenvironment, indicating the importance of new blood supply in endometriosis development. The local neovascularization is augmented by the complex mixture of growth factors, proangiogenic factors, steroid hormones, inflammatory cytokines present in peritoneal fluid [54]. Many pro-angiogenic factors, including fibroblast growth factors (FGF), platelet-derived endothelial cell growth factor(PDGF), transforming growth factor-alpha and beta (TGF-αx and TGF-β), hepatocyte growth factor(HGF), erythropoietin, angiogenin, tumor necrosis factor-alpha (TNF-c), and IL-8 have been detected at increased concentrations in peritoneal fluid of women with endometriosis [54]. Vascular endothelial growth factor (VEGF), produced in high amounts by activated peritoneal macrophages, neutrophils, lymphocytes, and endometrial stromal cells, is considered the most crucial angiogenic agent to induce proliferation and migration of endothelial cells, that can also increase vascular permeability [5556. VEGF is exerted in response to physiological activators, such as inflammation and hypoxia. Bone-marrow-derived endothelial progenitor cells detected in early-stage of endometriotic lesions are recruited by hypoxia-inducible-factor-alpha (HIF-1α) and stromal-cell-derived-factor 1(SDF-1)[57,58]. New agents, like antiangiogenic factors, could constitute a new and promising approach to treating this disease [59]. 

4.4. Immune Dysregulation

Inflammation has a vital role in the progression of endometriosis and is associated with altering the immune cell profile in the peritoneal cavity [33]. The endometrial tissue is a significant source of inflammatory mediators like cytokines, chemokines, and prostaglandins, which attract macrophages, neutrophils, monocytes, eosinophils, and T cells, that can affect processes in the abdominal cavity [60]. The peritoneal fluid of endometriosis is characterized by the enhanced concentration of inflammatory mediators like IL-1, IL-6, IL-8, TGF-β, TNF-α, VEGF, cyclooxygenase-2(COX-2), and monocyte chemoattractant protein 1 (MCP-1)[61,62]. Changes in inflammatory mediators result from the aberrant function of almost all types of immune cells in women with endometriosis.

Peritoneal macrophages are the most prevalent immune cells, found in the highest quantity in the peritoneal fluids. The peritoneal environment is regulated by the activated macrophages, which can scavenge cellular debris, and remove red blood cells and damaged tissue fragments. Lesion resident macrophages can induce tissue repair, inflammation, and angiogenesis through the secretion of soluble mediators like cytokines, prostaglandins, and enzymes. However, in the peritoneum of endometriosis-affected women, macrophages have a decreased phagocytic activity, and the amount of regurgitated endometrial cells in the peritoneal cavity may be higher. The imbalance in M1 and M2 macrophages was reported in endometriosis with an upregulation of the M2 type. M2 macrophages are supposed to have a crucial role in endometriosis development by modulating adaptive immune response and, consequently, promoting the implantation and proliferation of endometrial cells [33]. Macrophage-derived factors such as prostaglandins and cytokines produced in the peritoneal cavity may also modulate natural killer cells activity [63]. The cytotoxic function of NK cells against endometrial cells reaching the peritoneal cavity is decreased and is inversely related to the advanced stages of the disease [64]. Moreover, reduced T cells cytotoxic activity, modulation of pro-inflammatory cytokine secretion, and altering The cytokine profile prevalent in the early stages of the disease, to a Th2 cytokine profile in late stages and autoantibody production by B lymphocytes were observed [8,65]. The presence of this altered inflammatory niche could favor the implantation and development of endometriotic lesions from refluxed endometrial tissue. There is substantial evidence that the immune system plays a crucial role in this disease. Novel treatment strategies targeting immune pathways are urgently needed [13].

4.5. Oxidative Stress

Oxidative stress occurs due to an imbalance between reactive oxygen/nitrogen species (ROS/RNS)production and the organism's ability to scavenge and detoxify ROS/RNS harmful effects [66]. Essential molecules in the body, such as membrane lipids, nucleic acids, and proteins, are ROS targets. Oxidative stress is involved in the pathogenesis of many chronic diseases, such as cancer, neurodegenerative and cardiovascular diseases, and aging [67]. Endometriosis may involve ROS production because macrophages, erythrocytes, and apoptotic endometrial tissue, transplanted into the peritoneal cavity through retrograde menstruation, are found to be inducers of oxidative stress. The accumulation of iron in the different components of the peritoneal cavity of endometriosis patients has been reported. Peritoneal iron overload may be a consequence of hemoglobin breakdown or bleeding of peritoneal lesions. The macrophages and lymphocytes are recruited and activated by releasing the proinflammatory heme products and the oxidative stress signals. Enhanced activity of peritoneal macrophages and lymphocytes, in turn, strengthens the oxidation stress in the endometriotic peritoneum [68]. Moreover, ROS activates NF-kB, which leads to the expression of multiple genes engaged in cell growth, angiogenesis, and inflammation mechanisms regulation in endometriosis [69]. A subclass of nitrogen-containing compounds can play detrimental effects in endometriosis pathology. In women with endometriosis, the increased concentration of endothelial and inducible forms of nitric oxide synthase (eNOS and iNOS), the enzymes that ultimately produce nitric oxide (NO), has been found in the peritoneal fluid. In endometriosis conditions, the elevated levels of NOS and NO are correlated with impaired reproductive biological processes, e.g., ovulation, fertilization, implantation, and embryonic development. Moreover, the increased endometriosis-related eNOS activity has shown a positive correlation between estrogen and progesterone levels [70]. Additionally, aberrant changes in the potential of endogenous antioxidant enzymes like superoxide dismutase (SOD) and glutathione peroxidase(GPX) can contribute to the oxidative damage that occurs in endometriosis [70]. Estrogen participates in the SOD induction to overcome the excessive oxidative stress; however, overexpression of this antioxidant enzyme has adverse effects and contributes to promoting endometriotic cell survival and protecting them from apoptosis. Superoxide anion produced in large amounts mediates several signaling pathways and contributes to endometriosis-related pain through activation of nociceptive neurons [71]. Oxidative stress has been suggested as an etiological factor of chronic pelvic pain, and antioxidant supplementation has a proven impact on reducing pain in endometriosis patients [72]. These findings highlight the importance of developing therapeutic approaches targeting oxidative imbalance: reducing the oxidative stress status may exert protective effects against endometriosis.

4.6. Hormonal Imbalance

Hormonal imbalance in endometriosis is the master regulator of the alternations of multiple cellular functions, such as proliferation, invasion, angiogenesis, inflammation, neurogenesis, and pain generation[55]. Endometrial tissues are controlled by steroid hormones like 17β-estradiol and progesterone, which change the expression of hundreds of genes during different phases of the menstrual cycle. Eutopic endometrial tissues and endometriotic tissues in ectopic locations contain the immunoreactive estrogen receptors and progesterone receptors (PR); therefore, they respond to 17β-estradiol and progesterone with apparently similar histological changes[73]. Local estrogen production in both the ectopic and eutopic endometrium is considered to stimulate tissue growth and play a crucial role in regulating the immunological mechanisms responsible for controlling the development of endometriosis. The enzyme aromatase, a member of the cytochrome P450 superfamily, is responsible for the last step in the synthesis of estradiol through the aromatization of androgens (androstenedione and testosterone) into estrogens (estrone and estradiol, respectively)[74]. In premenopausal women with endometriosis, estradiol arises from three major tissue sites that express aromatase. These are ovaries, which primarily convert cholesterol to estradiol and secrete it periodically into the circulation, peripheral tissues such as the adipose tissue and skin, that convert androstenedione to estrone in relatively small quantities, and endometriotic tissue, synthesizing de novo high amounts of estradiol from cholesterol via aromatase and steroidogenic acute regulatory protein (StAR)[73]. Contrary to endometriotic lesions, normal endometrium cannot synthesize estrogen due to these enzymes' absence [75]. In endometriosis, local estradiol levels increase due to upregulation of estradiol-producing aromatase expression and reduction in 17β-HSD type 2 activity, implicated in the inactivation of estradiol through the oxidation to less active estrone [76]. In normal conditions, the expression of 17β-HSD type 2 in epithelial cells is activated by paracrine signaling triggering by the progesterone via PRs on stromal cells. There are two isoforms of PRs: PR-A and PR-B; PR-B likely plays a more crucial biological function in the endometrium. Progesterone resistance in endometriotic tissue is due to the total reduction in PRs and a drastic downregulation of PR-B in endometriotic stromal cells [77J. In the case of estrogen receptors (ER), a significant reduction in isotype ERα and an increase in ERβ is observed. The elevated expression of ERβ is associated with its promoter hypomethylation, while the decrease in ERα is due to its promoter hypermethylation and direct inhibition by ERβ [78]. Increasing the E2/ERβratio is considered to enhance lesion survival and inflammation. It is linked with the positive feedback loop by stimulation of COX-2 activation, which is involved in producing hormones, such as prostaglandin E,(PGE,), with significance in inflammation and pain. In turn, PGE2 influences steroidogenic genes, mainly overexpressing aromatase, and supports the sustained production of estradiol [78,79]. Novel alternative treatment to regulate estradiol biosynthesis and modulate its coactivators without suppressing ovulation, instead of conventional pharmacotherapy, could be designed to control this disorder. The substances that bind competitively to ERs, such as phytoestrogens, are recommended for future research assessment to demonstrate their effect on the levels of hormones and inflammatory markers in endometriosis.

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