**1. Introduction**

276 Endometriosis - Basic Concepts and Current Research Trends

Zhou Y.; Gan Y. & Taylor H. S. (2011). Cigarette smoke inhibits recruitment of bone-

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marrow-derived stem cells to the uterus. *Reproductive Toxicology,* Vol. 31, No. 2,

Endometriosis is a common gynaecological disease, defined by the presence of endometrial tissue outside the uterus, causing pain and infertility of women in reproductive age (Galle, 1989). It is estimated that it occurs in 10-15% for women in the reproductive age and more than 30% of all infertile women are affected (Cramer *et al.*, 2002). However, the actual figure on the total prevalence may even be higher, as the disease is often not diagnosed due to heterogenous clinical manifestations. These manifestations include dysmenorrhoea, dyspareunia, dysuria and chronic abdominal or pelvic pain as well as infertility, resulting in a severely limited quality of life (Davis *et al.*, 2003; Milingos *et al.*, 2006; Vercellini *et al.*, 2007). Thus, the aim on treating endometriosis should ideally target the endometriosis itself, i.e. relieves pain, promotes fertility and prevents reocurrence. Unfortunately, there is no current treatment being able to fulfill all these requirements. All conservative treatments, either medical or surgical, are still liable for disease reocurrence, and they do not address the cause and possible side effects brought upon to the disease mechanism and the patient outcomes.

In this chapter, we will analyze the rationale and limitations of the current therapy of endometriosis. Also, we will discuss on the latest therapies that hold a higher efficacy and sensitivity on treating the disease. Most importantly, we will highlight the effect of green tea on being a potential remedy toward tackling endometriosis.

#### **1.1 Current and new treatment**

In the past, the disease was best thought to be treated surgically. And with the advancement of operative laparoscopy, the treatment of endometriosis could be started as soon as it was diagnosis. However, different researches have shown surgical removal of endometriosis can bought upon many complications and chronicity. Likewise, without medical supplements, the patients would have a high chance for disease reocurrence. Hence, there is a great demand for medical treatments that can induce a suppression of this disease.

The type of treatments offer would depend on the extent or stage of the disease, the amount of pain suffered, and fertility wanted (Valle *et al.*, 2003) (Fig. 1). To perform the best therapy would require complete diagnosis and inspections of the lesion to determine the symptoms and staging of the patient's endometriosis (Olive *et al.*, 2001). The choices of present treatments include expectant management, medical therapy and surgical treatment (Table 1).

Green Tea for Endometriosis 279

In asymptomatic patients, those with mild symptoms or infertility with minimal endometriosis, expectant management may be prescribed. These women may opt for birth control pills because they can prevent endometriosis from progressing and protect against unwanted pregnancy (Bedaiwy *et al.*, 2009). While for women approaching the menopause, they may also be managed expectantly, because the growth of endometriosis is suppressed

Medical therapies are typically used for patients with endometriosis that have minimal pelvic pain. The types of medical therapies can be divided into two main categories: analgesics and hormonal. However, medical therapy alone is not appropriate for women with more advanced stages of endometriosis or those desiring pregnancy. And unlike surgery, medical therapy does not enhance your chances of conception (Hansen *et al.*, 2006).

Analgesics treatments are often the first-line therapy in women with primary dysmenorrhea or pelvic pain and those with minimal pain symptoms associated with endometriosis. For mild cases of endometriosis, analgesic medications alone may be sufficient to relieve symptoms (Mahutte *et al.*, 2003). Commonly used analgesic medications include paracetamol and non-steroidal anti-inflammatory drugs (NSAID). Although the use of analgesic treatments for pain relief is regularly prescribed, lack of clinical studies have

Hormonal treatments are aimed at decreasing the amount of estrogen in the body, which will inhibit the progression of the endometrial implants (Coutinho, 1982). The most common hormonal medications used are combined oral contraceptives, progestins, androgens, and gonadotropin-releasing hormone (GnRH) agonist analogs. Combined oral contraceptives has been used for women with endometriosis since the 1950s (Kistner, 1959). These pills consist of a low combination of synthetic estrogen and progesterone. They have been shown to be very effective for patients with mild symptoms of endometriosis (Vercellini *et al.*, 1993; Vessey *et al.*, 1993). The main advantages are that it is inexpensive and is usually reasonably well tolerated by women (Kennedy, 2004). It can also be taken safely for many years if necessary (Kennedy, 2004). However, it is not free of side effects. These include irregular vaginal bleeding, fluid retention, abdominal bloating, weight gain, increased appetite,

Progestins are a group of drugs that behave like the female hormone progesterone. Although the actual mechanism on how progestins relieve the symptoms of endometriosis remained unclear, a possible effect might be the growth of endometrial implants was suppressed by this hormone, causing them to gradually regress (Schweppe, 2001). Other reported that they may reduce endometriosis-induced inflammation in the pelvic cavity (Vercellini *et al.*, 2003). In clinical trials, it showed progestins being effective treatments for the symptoms of endometriosis (Kennedy *et al.*, 2005). When taken continuously daily, they have shown to relieve endometriosis-associated pain as effectively as the other hormonal drugs (Kennedy *et al.*, 2005). However, there are side effects, which include irregular menstrual cycle, sore breasts,

**1.1.1 Expectant management**

after the menopause.

**1.1.2 Medical therapy**

**<IP_ADDRESS> Analgesics**

**<IP_ADDRESS> Hormonal**

critically evaluated their effectiveness.

nausea, headaches, breast tenderness and depression.

#### Traditional treatment

Expectant Management

Surgical Treatment

New treatment

Angiogenesis inhibitors Antioxidant therapy Aromatase inhibitors Tumor necrosis factor-alpha inhibitors Matrix metalloproteinase inhibitors Immunomodulators Traditional Chinese medicines

Table 1. Treatment of Endometriosis

Fig. 1. Clinical evaluation on patients with endometriosis

Traditional treatment Expectant Management Medical Therapy - Analgesics - Hormonal

Surgical Treatment - Conservative Surgery - Definitive Surgery

New treatment

Angiogenesis inhibitors Antioxidant therapy Aromatase inhibitors

Immunomodulators

Tumor necrosis factor-alpha inhibitors Matrix metalloproteinase inhibitors

Fig. 1. Clinical evaluation on patients with endometriosis

Traditional Chinese medicines Table 1. Treatment of Endometriosis

#### **1.1.1 Expectant management**

In asymptomatic patients, those with mild symptoms or infertility with minimal endometriosis, expectant management may be prescribed. These women may opt for birth control pills because they can prevent endometriosis from progressing and protect against unwanted pregnancy (Bedaiwy *et al.*, 2009). While for women approaching the menopause, they may also be managed expectantly, because the growth of endometriosis is suppressed after the menopause.

#### **1.1.2 Medical therapy**

Medical therapies are typically used for patients with endometriosis that have minimal pelvic pain. The types of medical therapies can be divided into two main categories: analgesics and hormonal. However, medical therapy alone is not appropriate for women with more advanced stages of endometriosis or those desiring pregnancy. And unlike surgery, medical therapy does not enhance your chances of conception (Hansen *et al.*, 2006).

#### **<IP_ADDRESS> Analgesics**

Analgesics treatments are often the first-line therapy in women with primary dysmenorrhea or pelvic pain and those with minimal pain symptoms associated with endometriosis. For mild cases of endometriosis, analgesic medications alone may be sufficient to relieve symptoms (Mahutte *et al.*, 2003). Commonly used analgesic medications include paracetamol and non-steroidal anti-inflammatory drugs (NSAID). Although the use of analgesic treatments for pain relief is regularly prescribed, lack of clinical studies have critically evaluated their effectiveness.

#### **<IP_ADDRESS> Hormonal**

Hormonal treatments are aimed at decreasing the amount of estrogen in the body, which will inhibit the progression of the endometrial implants (Coutinho, 1982). The most common hormonal medications used are combined oral contraceptives, progestins, androgens, and gonadotropin-releasing hormone (GnRH) agonist analogs. Combined oral contraceptives has been used for women with endometriosis since the 1950s (Kistner, 1959). These pills consist of a low combination of synthetic estrogen and progesterone. They have been shown to be very effective for patients with mild symptoms of endometriosis (Vercellini *et al.*, 1993; Vessey *et al.*, 1993). The main advantages are that it is inexpensive and is usually reasonably well tolerated by women (Kennedy, 2004). It can also be taken safely for many years if necessary (Kennedy, 2004). However, it is not free of side effects. These include irregular vaginal bleeding, fluid retention, abdominal bloating, weight gain, increased appetite, nausea, headaches, breast tenderness and depression.

Progestins are a group of drugs that behave like the female hormone progesterone. Although the actual mechanism on how progestins relieve the symptoms of endometriosis remained unclear, a possible effect might be the growth of endometrial implants was suppressed by this hormone, causing them to gradually regress (Schweppe, 2001). Other reported that they may reduce endometriosis-induced inflammation in the pelvic cavity (Vercellini *et al.*, 2003). In clinical trials, it showed progestins being effective treatments for the symptoms of endometriosis (Kennedy *et al.*, 2005). When taken continuously daily, they have shown to relieve endometriosis-associated pain as effectively as the other hormonal drugs (Kennedy *et al.*, 2005). However, there are side effects, which include irregular menstrual cycle, sore breasts,

Green Tea for Endometriosis 281

estrogen medication would be given to prevent menopausal symptoms to occur in the patients. Likewise, woman who underwent oophorectomy for endometriosis has greater pain relief and less likelihood of repeated surgery than those operated by hysterectomy with ovarian preservation (Namnoum *et al.*, 1995). In addition, the rate of recurrence in patients

Recently, with the better understanding on the pathogenesis and progression toward endometriosis, novel medications on using molecular targets are developed for treatment of endometriosis. The advantages of such agents hold a higher efficacy and sensitivity on treating the disease, while minimizing evidence of side effects experienced by the patients.

One of the main etiologies of endometriosis is believe to be resulted from implantation of retrograde shed endometrium during menstruation (Sampson, 1927). The properties of the endometrium have the capacity to adhere, attach, and implant ectopically (Koks *et al.*, 1999; Maas *et al.*, 2001). Based on the anatomical surrounding, endometriotic lesions are found to be larger in size with the availability to rich blood supply. This suggesting that angiogenesis

The use of angiostatic agents may provide a new therapeutic option to inhibit this pathological process. The aim is to mainly control two processes involved in angiogenesis: endothelial cell growth and endothelial cell adhesion. Angiogenic cytokines are elevated in the peritoneal fluid in patients with endometriosis (Nisolle *et al.*, 1993). Anti-angiogenesis therapies have been shown effective in suppressing the development in endometriotic lesion in mice (Nap *et al.*, 2004). Common angiostatic compounds, such as anti-human vascular endothelial growth factor-A (anti-hVEGF), TNP-470, endostatin, and anginex, significantly decreased microvessel density and inhibited the established endometriosis lesions (Dabrosin *et al.*, 2002; Nap *et al.*, 2004; Yagyu *et al.*, 2005). By far, the only clinical trial conducted with an anti-angiogenesis therapy on treating endometriosis-associated pain was thalidomide (Scarpellini *et al.*, 2002). Although the result showed promising pain relief in the patients, however, thalidomide is a potential teratogen (Khoury *et al.*, 1987). Thus, women wanting pregnancy is prohibited.

Although the actual etiology of endometriosis remains unknown, it is widely accepted that retrograde menstruation is associated with endometriosis. However, it is unclear on why only a portion of women with retrograde menstruation develops endometriosis, while others do not. Studies proposed this might be due to the presence of elements such as macrophages, iron or environmental contaminants disrupting the balance between ROS and antioxidants in the peritoneal fluid of some women, leading to oxidative stress and endometriosis (Arumugam *et al.*, 1995; Donnez *et al.*, 2002; Murphy *et al.*, 1998). Likewise, the cyclical changes in the endometrium are accompanied by changes in the expression of

Patients with endometriosis have shown the increase in generation of ROS by peritoneal fluid macrophages, with increased lipid peroxidation (Halme *et al.*, 1983). The diminished peritoneal fluid antioxidants (Murphy *et al.*, 1998), elevated oxidized lipoproteins, lysophosphatidyl choline (Murphy *et al.*, 1998), and other markers of lipid peroxidation

various antioxidant enzymes in the endometrium (Gurdol *et al.*, 1997).

with definitive surgery is much lower than in those with conservative surgery.

**1.1.4 Latest treatments developed against endometriosis**

is prerequisite for the development of endometriosis.

**<IP_ADDRESS> Anti-angiogenesis inhibitors**

**<IP_ADDRESS> Anti-oxidant therapy**

headache, nausea, dizziness and bloating. These side effects are not usually serious and longlasting (Winkel *et al.*, 2001), however many patients still feel unpleasant and difficult to cope with. Hence, most women could seldom complete this type of treatment.

Danazol is an effective androgen for treating endometriosis. It works by suppressing the growth and development of the endometriotic lesion temporarily, hence continuous medication is required. Clinical trials have shown that danazol is effective in relieving the pain symptoms of endometriosis (Kennedy *et al.*, 2005) for approximately 90% of women (Biberoglu *et al.*, 1981). However, common side effects from these treatments include acne, oily skin, increased hair growth, and weight gain. Its unpleasant side effects and its risk of developing cardiovascular disease mean it is not the first choice of treatment for endometriosis (Kennedy, 2004).

Gonadotropin releasing hormone (GnRH) agonists are a group of drugs that have been used to treat women with endometriosis for many years (Schweppe, 2005). They work by stopping the production of estrogen by a series of inhibition on the estrogen-related pathway mechanisms. Although this treatment can reduce 50% in symptoms, but in longterm, pain recurrence can be observed in up to 75% of the cases (Surrey *et al.*, 2002). Likewise, affecting the estrogen hormonal cycle can result in major side effects like bone thinning (Pierce *et al.*, 2000).