**3.2.3 Anti-inflammatory**

Cytokines are a group of multifunctional proteins that mediate the regulation of inflammatory responses. These cytokines are expressed in a number of tissues, including macrophages, vascular endothelial cells, adipose tissue and neurons. In general, the role of cytokines can be further classified depending on the way they influence inflammation, such as pro- or anti-inflammatory (Kundu *et al.*, 2008). Factors such as tumor necrosis factor-α, IL-6, IL-1, GM-CSF, interferon-c, and IL-12 played a major role on the induction of the inflammatory response.

EGCG has been shown to possess anti-inflammatory properties *in vivo* and *in vitro* (Hamer *et al.*, 2007). The potent effects of tea polyphenols toward inflammation have also been known to cancer prevention (Beltz *et al.*, 2006). Tea polyphenols appear to modulate at different targets the anti-inflammatory activities related to arachidonic acid-dependent pathways, such as cyclooxygenase (COX) inhibition. Within the arachidonic acid-independent pathways, nitric-oxide synthase (NOS) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) are targets of polyphenols (Miles *et al.*, 2005). The released phytochemicals inhibit cyclooxygenase-2 (COX-2) and inducible nitric-oxide synthase (iNOS) expression by blocking NF-κB activation. Particularly EGCG suppresses activation of NF-κB by repression of degradation of inhibitory unit, IκBκ, which hampers subsequent nuclear translocation of the functionally active subunit of NF-κB (Kundu *et al.*, 2008).

#### **3.2.4 Anti-angiogenic**

It has been widely shown that green tea have the ability to inhibit angiogenesis in *in vitro* proliferation studies (Laschke *et al.*, 2008; Park *et al.*, 2006; Slivova *et al.*, 2005) and in *in vivo* angiogenesis assays (Laschke *et al.*, 2008; Xu *et al.*, 2009). Anti-angiogenesis plays a crucial role accounting to the cancer-preventive effect made by green tea. As angiogenesis is a complex multi-step process that includes the proliferation, migration and differentiation of endothelial cells into tube-like structures. The initiation of each step involves multiple

Green Tea for Endometriosis 289

Likewise, the possible toxicity by EGCG toward the reproductive organs was also investigated. The treatment marked by EGCG showed no adverse effect neither on

In another study conducted by our team, we demonstrated the anti-angiogenic effects of green tea catechin on a mouse model induced with endometriosis (Xu *et al.*, 2009). These immunosuppressent mice were induced with endometriosis by subcutaneously implanting human endometrial tissues from patients with endometriosis. Following the day of operation, endometriosis induced mice were treated daily with saline, Vitamin E or EGCG for two weeks. The result showed those treated with EGCG, but not Vitamin E, have the smallest size of lesion growth. Angiogenesis in lesions from the implant and adjacent tissues was under-developed, and microvessel size and density were lower. With regards to the lower expression of VEGF expression, EGCG significantly inhibits the development of experimental endometriosis can be through anti-angiogenic effects. Following on this study, we investigate the likely mechanism would involve the selective inhibition of angiogenic factors, mainly VEGF-C/VEGFR2 pathway by EGCG to suppress the growth of the endometriotic lesions (Xu *et al.*, 2011) (Fig 3). With these studies, the potential of green tea as an anti-angiogenic agent is high because of its

angiogenesis and blood perfusion nor tissue integrity of ovarian follicles.

low cost, wide availability, and apparent low toxicity.

Fig. 3. Summary of the mechanism of green tea for endometriosis

pleomorphic manifestations of endometriosis.

Endometriosis is one of the most common benign gynaecological conditions. It affects an estimated 176 million worldwide regardless to their ethnics and social background. And it is estimated that 30-40% of women with endometriosis may not be able to have children. However, there is currently no single etiology that can explain the pathogenesis and

**5. Conclusion** 

growth factors, proteases and adhesion molecule secreted by the endothelial cells, as well as supporting cells from the surrounding (Carmeliet *et al.*, 2000). Pathogenesis related to abnormal angiogenesis can be demonstrated in rheumatoid arthritis, diabetic retinopathy, and cancer growth and metastasis. Therefore, angiogenesis would be a crucial process that may account for part of the mechanisms of the cancer preventive effect of green tea. Studies have shown green tea's potential to decrease vital angiogenic factors in breast cancer (Sartippour *et al.*, 2002; Sartippour *et al.*, 2002). Similarly, other showed the mark decrease of IL-8 production by endothelial cells (Tang *et al.*, 2001). Likewise, tumor necrosis factor-α and matrix metalloprotinases were suppressed by the incorporation of EGCG (Annabi *et al.*, 2002; Yang *et al.*, 1998). The observation on the effect of green tea being anti-angiogenic is clinically very significant (Kabbinavar *et al.*, 2003). With the lack of information on clinical trials, work is still needed on promoting green tea as a possible medication on antiangiogenesis therapy.

#### **3.3 Side effects of green tea**

The preliminary efficacy results of a phase I–II clinical study from a cohort of non-cancer patients demonstrated no uncomfortable side effects (Choan *et al.*, 2005). To date, the only side effect reported from drinking green tea is to cause insomnia, increase heart rate and nausea in selected individual, due to the presence of caffeine. An average cup of tea (10 g of tea leaves in 1 L water) contains around 300 mg of crude solids with 30–42% catechins and 3–6% caffeine (Khan *et al.*, 2007). However, the amount of caffeine is three times less than that of drinking coffee. Thus, this makes drinking green tea a prospective and very safe treatment for clinical use.
