**1. Introduction**

Endometriosis is a chronic gynecological disorder defined as the presence of endometrial tissue in extrauterine sites. Normally, functional endometrial tissue is present outside the uterine cavity and results in symptoms that include pelvic pain, dysmenorrhea, and dyspareunia. Patients with endometriosis often experience infertility and are at an increased risk of epithelial ovarian cancer. Endometriosis can be classified into three subtypes: lesions in the pelvic peritoneum; ovarian endometriosis which may occur as superficial lesions on the surface of the ovary or as cysts lined with endometrioid epithelium (endometrioma); and deeply infiltrating lesions of the rectovaginal septum [1, 2]. Despite the prevalence of endometriosis and its significant impact on women's lives, there are relatively few in vitro and in vivo models available for studying the biology and pathophysiology of this complex disease, as well as for use in the preclinical development of new therapies [3, 4].

The most accepted theory describes that viable endometrial cells, expelled by the fallopian tubes, are able to survive in the peritoneal environment by binding to its membrane [5]. However, approximately 90% of women of reproductive age with leaky fallopian tubes experience retrograde menstruation, while the prevalence of endometriosis is estimated at 6–10% [6–9]. To discover the mechanisms and propose therapeutic approaches to endometriosis, various in vitro and in vivo models of the disease are frequently proposed [9–11]. The study of endometriosis mechanisms is complex and the research results obtained may vary among different researchers who apply various methods of material collection, inclusion criteria, and genetic profiles of the sample population [12]. Furthermore, the use of primary cells in endometriosis research is highly recommended as it is a multifactorial and heterogeneous disease that varies widely among patients [5, 13–20].

In recent years, advances in neuroendocrinology, endocrinology, tumorigenesis, neurogenesis, and genomics are transforming current approaches to treating endometriosis. In this regard, GnRH antagonists, SPRM/SERM, aromatase inhibitors, immunomodulators, and antiangiogenic drugs appear as emerging and promising medical treatments for endometriosis. More studies are needed to promote personalized medication for patients with endometriosis.

One of the approaches of interest to the treatment of endometriosis is phytotherapy. The use of medicinal plants individually or in association, in the form of decoctions, extracts, and purified bioactive compounds is a common practice in several countries [21–26]. Medicinal plants exhibit many properties, including anti-inflammatory, anti-angiogenic, anti-proliferative, proapoptotic, immunomodulatory, and estrogen modulating activities which can be explored

for the treatment of endometriosis or as a complementary therapy to overcome endometriosis-related symptoms [26–28]. Herbal medicines can be cheaper, easily accessible and well accepted by the population [21, 27, 28] in addition to valuing the national flora and traditions of different peoples.

Chinese herbal medicine as Xuefu Zhuyu decoction (XZD), Xiaochaihu decoction (XCHD), Qu Yi Kang (QYK), Yi Wei Ning (YWN), Yi Wei San (YWS), and Huoxue Xiaoyi decoction (HXD), which are composed of a mixture of different medicinal herbs, are widely used to relieve dysmenorrhea, reduce ectopic lesions and aid in the maintenance of fertility [21]. In general, these drugs inhibit adhesion, aggregation, and angiogenesis, reduce serum estradiol levels and inflammatory chemical mediators [21].

*Angelica sinensis* (Danggui), *Curcuma longa* (Jianghuang), *Pueraria lobata* (Gegen), *Salvia miltiorrhiza* (Danshen), *Paeonia lactiflora* Pall (Chishao) are some of the herbs commonly used in Chinese medicine prescriptions for dysmenorrhea and irregular menstruation due to endometriosis and which have antiangiogenic effects, including the regulation of the vascular endothelial growth factor (VEGF) [27, 29].

Additionally, bioactive compounds isolated from plants, including Epigallocatechin Gallate (catechin, *Camelia sinensis*, green and black teas), Curcumin (hydrophobic polyphenol, *Curcuma longa*), Puerarin (isoflavone from roots of *Pueraria spp*), Ginsenoside Rg3 (kind of steroid glycosides, and triterpene saponins, genus *Panax*), Resveratrol (a natural phytoalexin, mainly extracted from grapes), Genistein (isoflavone isolated from soy); Xanthohumol (*Humulus lupulus*), Naringenin (flavanones group, found in citrus and grapes) have been evaluated for the treatment of endometriosis in *in vivo* and *in vitro* models, as well as clinical trials [21, 27–31]. The actions of these bioactive compounds involve reducing the expression of VEGF, matrix metalloproteinases (MMP2 and MMP9), intercellular adhesion molecule 1 (ICAM-1) and cytokines as tumor necrosis factor-alpha (TNF-α), interleukins (IL-6 and IL-8) and monocyte chemoattractant protein 1(MCP-1) [21, 26–30].

Using bioinformatics and data mining various combinations and mechanisms of action of Chinese herbal medicines were analyzed to establish interactions with multiple targets. These studies showed that, among other findings, Chinese herbal medicines could regulate various signaling pathways including VEGF, nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT), and hypoxia-inducible factor 1 (HIF-1) [32].

In the search for new therapeutic strategies, experimental models are useful tools for understanding the effects, mechanisms of action, and safety in the use of medicinal herbs in endometriosis. However, they do not replace clinical trials, even less explored. In view of the vast literature and in order not to be exhaustive, below, only some of the investigations on herbal medicines and bioactive compounds are presented, as an example of the possibilities of treatments for endometriosis.

Regarding the traditional Chinese medicine, low and high doses of Gui Xiong Xiaoyi Wan (GXXYW), a formula that contains a combination of 14 types of plants, orally given for 28 days to rats surgically-induced endometriosis, were able to reduce the volume of the lesion, inhibit cell proliferation, induce apoptosis of endometriotic cells, as well to regulate the cell-mediated immune response by increasing the CD4:CD8 lymphocytes ratio [33]. The reduced size of the endometriotic implants was also observed for Hua Yu Xiao Zheng (HYXZ) decoction, a mixture of 13 plants, which were used in a rat endometriosis model, administered by oral gavage at three different doses. HYXZ effects are associated with decreased protein and mRNA levels of VEGF and angiopoietin 2 (Ang-2) [34].

#### *Introductory Chapter: Endometriosis - Recent Advances, New Perspectives and Treatments DOI: http://dx.doi.org/10.5772/intechopen.103820*

Through nuclear magnetic resonance spectroscopy-based metabolomics, the Gui-Zhi-Fu-Ling-Capsules (GZFLC), a classic Chinese medicinal formula composed of five herbs was studied in experimental endometriosis. This study pointed out that GZFLC regulates endometriosis by modulating metabolites changes of glycolysis or gluconeogenesis and then the expression of transforming growth factor-beta 1 (TGF-β1), glucose transporter-4 (GLUT-4), and VEGF [35]. Network pharmacology and mRNA transcriptome analysis were performed to study ELeng Capsule (ELC), another Chinese medicine formula that has been used for the treatment of endometriosis [36]. Based on network pharmacology, the ELC mechanisms involve neuroactive ligand-receptor interaction, toll-like receptor, VEGF and MAPK signaling pathways related to apoptosis, angiogenesis inhibition, and immune regulation. Moreover, based on RNA-sequence analysis, ELC effects were related to regulation of cytoskeleton, epithelial-mesenchymal transition, and focal adhesion [36].

In a clinical trial, a formulation containing five Chinese medicinal plants was orally taken by post-operative women with stage III-IV endometriosis after conservative surgery, at one dosage a day for 12 consecutive weeks, and compared with anterior abdominal subcutaneous injection with goserelin acetate sustained-release depot, at the dosage of 3.6 mg once every 28 days also for 12 weeks [37]. Serum levels of cancer antigen 125 (CA-125) and IL-18 were decreased by both treatments, but between them, CA-125 levels were reduced in the herbal treated women, pointing out the effects of Chinese medicinal plants in preventing the recurrence of stage III-IV endometriosis after conservative surgery [37].

Besides Chinese medicine, several other plant extracts and bioactive compounds have been explored in preclinical investigations. *Salvia miltiorrhiza* extracts were studied in a rat endometriosis model with interesting effects as decreased serum levels of CA-125 while in peritoneal fluids IL-18 and TNF-α were reduced and IL-13, an anti-inflammatory cytokine, was increased [38]. Extracts and extracts subfractions of *Anthemis austriaca* flowers, a Turkey native plant, were applied to treat rats after surgically-induced endometriosis. Adhesion scores, endometriotic implant volumes, TNF-a, VEGF, and IL-6 levels decreased after treatments with ethyl acetate and methanol extracts and methanol subfractions. These actions may be related to flavonoids and sterols [31].

The root aqueous extract of *Entada Africana* (EA), administered at three different doses and periods, was also evaluated in an experimental model of endometriosis and indicated EA as a potential treatment of pelvic pain and female infertility. EA decreased endometrial implant volume, dysmenorrhea, prevented the progress of endometriosis by increasing the activity of catalase in endometrial implants as well as promoted ovarian follicle growth, and prevented anovulation [22]. Similarly, the ethanol extract of *Persea americana* (avocado) seeds was orally administered at different doses to treat rats with endometriosis. Again, decreased endometrial implant volume was observed, in addition to reduced ectopic endometrium heigh. Moreover, serum levels of estradiol and progesterone and luteinized unruptured follicles were reduced while the number of antral follicles and corpora lutea increased, indicating the beneficial effects of the extract [24]. Furthermore, decreased endometriotic implants volume and intra-abdominal adhesions were observed by treatment with ethyl acetate and methanol extracts obtained from flowers of *Teucrium chamaedrys* L. These effects are probably associated with secondary metabolites of nonpolar and polar features in the extracts [39].

The beneficial action of *Allium sativum* (garlic) extract on reducing the symptoms of endometriosis was clinically evaluated. The patients received usual care supplemented by a garlic tablet (400 mg of dried garlic powder; 1100 μg of allicin) daily and were followed up for 3 months. Garlic tablets reduced pelvic and back pain, dysmenorrhea, and dyspareunia [25].

The molecular docking for active ingredients of *Scurrula atropurpurea* showed that among the nine studied ingredients which can interact with the complex NF-κB/inhibitor of nuclear factor-κB (IκB), Rutin showed the strongest interaction and therefore the greatest anti-inflammatory potential [23]. However, when pure Rutin and *Uncaria guianensis* aqueous extracts obtained from bark, roots, and leaves were tested, alone or in combination, in primary stromal cells isolated from patients with and without endometriosis, using two- and three-dimensional culture models, they increased pro-inflammatory cytokines, growth factors levels, and reactive oxygen species (ROS) production. The authors speculate that cell death might increase with longer treatment time. Another consideration is that stromal and epithelial cells are present in endometriosis and the study was performed only with stromal cells [40]. Differently, in surgically-induced endometriosis, Rutin treatment enhanced apoptosis, especially at higher doses, by reducing B-cell lymphoma protein 2 (Bcl-2) and increasing Bcl-2-associated X (Bax) and cleaved caspase 9. The compound was also effective in increasing antioxidants concentrations [41].

Regarding other phytochemicals, the therapeutic potential of Curcumina was evaluated in primary cultures of stromal cells derived from eutopic endometrium of endometriosis and normal endometrial stromal cells. In a dose-dependently manner and over the time course Curcumina abrogated various chemokines, cytokines, and growth factors secretion, besides decreasing phosphorylation of the inhibitor of NF-κB kinase subunit α/β (IKKα/β), NF-κB, signal transducer and activator of transcription 3 (STAT3), and Jun N-terminal kinase (JNK) signaling molecules [42]. In addition, the treatment of rats with a protoberberine-rich fraction obtained from *Chelidonium majus* L. in an endometriosis model prevented the reoccurrence of endometriosis and positively regulated the metabolism of glucose, lactate, and glutamate [43].

As described, there are a large number of herbal medicines already in use, but which need more clinical tests to better understand their effects and mechanisms of action. Additionally, many other medicinal herbs and bioactive compounds derived from them with potential application in endometriosis are under investigation and many others can still be studied. It is important to highlight that, although extremely useful, studies in experimental models need the complementation of clinical trials so that the results can be effectively understood. These researches, associated with the enormous wealth of plant-derived products, and based on traditional knowledge, may provide new therapeutic alternatives suitable for different stages of the disease and diverse populations, which encourages the continuity of studies of herbal medicines in the management of endometriosis.

*Introductory Chapter: Endometriosis - Recent Advances, New Perspectives and Treatments DOI: http://dx.doi.org/10.5772/intechopen.103820*
