**4. Green tea for endometriosis**

As already proven, the catechins, notably EGCG, found in green tea are potential candidates to inhibit the growth of tumors (Jung *et al.*, 2001; Nakachi *et al.*, 1998; Uesato *et al.*, 2001). They act as a pleiotropic substance, which influencing multiple mechanisms that are involved in carcinogenesis (Beltz *et al.*, 2006; Khan *et al.*, 2006) through suppressing angiogenesis (Kondo *et al.*, 2002; Zhu *et al.*, 2007). With these basic finding, recent direction pointed out that the anti-angiogenic and anti-oxidation properties of ECGC may be a promising therapeutic agent in treating endometriosis.

So far, there are two major groups studying the use of EGCG to relate with the inhibition of endometriosis (Laschke *et al.*, 2008; Xu *et al.*, 2009). In the study conducted by Laschke *et al.*, the study showed that EGCG suppresses E2-stimulated activation, proliferation and VEGF expression of endometrial cells *in vitro*. While in the *in vivo* study using dorsal skinfold chamber model, EGCG selectively inhibited angiogenesis and blood perfusion of endometriotic lesions. Similarly, histology of the endometriotic lesion revealed induced regression when EGCG was prescribed. The author proposed the possible mechanism on the inhibition on the growth of the lesion may be due to attenuation of VEGF expression by EGCG in cultured endothelial cells, with the stimulation with estrogen. This indicates that EGCG specifically blocks the E2-induced activation in endometrial cells, which EGCG would compete with E2 for binding to estrogen receptors. In addition, the study found that EGCG treatment may not only induce regression of endometriotic lesions, but may also have a positive anti-angiogenic effect on the eutopic endometrium of endometriosis patients. This was shown by the decrease in VEGF expression in the eutopic endometrium.

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 anti-

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

As already proven, the catechins, notably EGCG, found in green tea are potential candidates to inhibit the growth of tumors (Jung *et al.*, 2001; Nakachi *et al.*, 1998; Uesato *et al.*, 2001). They act as a pleiotropic substance, which influencing multiple mechanisms that are involved in carcinogenesis (Beltz *et al.*, 2006; Khan *et al.*, 2006) through suppressing angiogenesis (Kondo *et al.*, 2002; Zhu *et al.*, 2007). With these basic finding, recent direction pointed out that the anti-angiogenic and anti-oxidation properties of ECGC may be a

So far, there are two major groups studying the use of EGCG to relate with the inhibition of endometriosis (Laschke *et al.*, 2008; Xu *et al.*, 2009). In the study conducted by Laschke *et al.*, the study showed that EGCG suppresses E2-stimulated activation, proliferation and VEGF expression of endometrial cells *in vitro*. While in the *in vivo* study using dorsal skinfold chamber model, EGCG selectively inhibited angiogenesis and blood perfusion of endometriotic lesions. Similarly, histology of the endometriotic lesion revealed induced regression when EGCG was prescribed. The author proposed the possible mechanism on the inhibition on the growth of the lesion may be due to attenuation of VEGF expression by EGCG in cultured endothelial cells, with the stimulation with estrogen. This indicates that EGCG specifically blocks the E2-induced activation in endometrial cells, which EGCG would compete with E2 for binding to estrogen receptors. In addition, the study found that EGCG treatment may not only induce regression of endometriotic lesions, but may also have a positive anti-angiogenic effect on the eutopic endometrium of endometriosis patients. This was shown by the decrease in VEGF expression in the eutopic endometrium.

angiogenesis therapy.

**3.3 Side effects of green tea** 

treatment for clinical use.

**4. Green tea for endometriosis** 

promising therapeutic agent in treating endometriosis.

Likewise, the possible toxicity by EGCG toward the reproductive organs was also investigated. The treatment marked by EGCG showed no adverse effect neither on angiogenesis and blood perfusion nor tissue integrity of ovarian follicles.

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 low cost, wide availability, and apparent low toxicity.

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