**2. Non hormonal medical therapy**

#### **2.1 Non-steroidal anti- inflammatory agents**

With attention to inflammatory nature of endometriosis, for decades non- steroidal antiinflammatory agents (NSAIDs) such as naproxen and ibuprofen have been administrated for pain control, in endometriosis. These drugs have been reduced prostaglandins (PGs) production, the main stimulator factor in peritoneal nerves and decrease the nociceptor input messenger from the peritoneal endometriotic implants into central nervous system. Their gastrointestinal upsets and inhibition of ovulation (Duffy &Stouffer,2002) against low cost and easy availability, always puts NSAIDs in a challenging situation; rather than, new NSAIDs as a selective cyclooxygenase (COX)-2 inhibitors like celecoxib without any effect on PG pathway, could induce apoptosis in endometriotic implants (Seo etal,2010). However

Medical Treatment in Endometriosis 477

Oral combined contraceptive pills induce atrophy in peritoneal endometriotic implants by initial decidualization effect like a pseudo pregnancy situation; perhaps they could increase the apoptosis in endometriotic implants (Meresman etal , 2000). OCPs are the most prescripted drugs in endometriosis, especially in minimal and mild stages of disease for pain control ; although there is a new report about the effectiveness of OCPs usage in patients with deep endometriotic nodules (advance stage) (Mabrouk etal,2011) ,which eliminate the effectiveness of OCPs administration only in early stages of disease. In addition, there is not any differences between various available formulations in pain relief potency and any kind of OCPs which had 30-35µg of ethinyl estradiol could be used and there is no necessity for high dose (HD) contraceptive administration (with 50 µg of ethinyl estradiol) (Davis etal,2007) . About the usage methods has been shown that, continues usage had better clinical results rather than cyclic administration (Harada etal,2008). In cases of sever atrophy of endometrium and break through bleeding, supplemental estrogen for 7-10

Progestins at the first stage of administration induce decidualization in endometriotic tissues and at the second phase by proliferation inhibition makes atrophia. Also, progestins make depletion in estrogen receptors and inhibit their activation (Kirkland etal, 1992). Progestins could induce transformation of potent form of estrogens (estradiol) to weaker product (estrone) (Tseng etal, 1981) .In recent studies discover that there are two important catalyzer enzymes which metabolize progesterone in endometriotic implants. Aldo-Keto reductase 1C1 and 1C3 (AKR1C1 & AKR1C3) had significant up-regulation expression in ovarian endometriosis which interfere with inhibitory effects of human progesterone (Hevir etal, 2011). It found that exogenous progestins administration could inhibit their activity (Beranic etal, 2011).Various available progestins could be used: oral, parenteral, intrauterine device and implants. With higher dosage of administrated progestins, another effective role of them could be achieved: inhibition of matrix metalloproteinase (Osteen etal , 2003). Most of the time the clinical response to progestins are like the oral contraceptive pills (Schlaff etal,2006), without significant side effects except breakthrough bleeding which can be managed with short time, low dose estrogen administration. Also, the probably bone loss effect is reversible (Cundy etal,1996).The levonorgestrel releasing intrauterine device (LNG-IUS) is a valuable therapeutic option especially for women with deep infiltrative endometriotic implants (Lochat etal,2005).About the pain relief efficacy of progestin subdermal implants (Implanon) evidences are limited than other therapeutic modalities

Gonadotropin –releasing hormone (GnRH) agonists are synthetic drugs which are resistant to degeneration in body and are produced by some variation in amino acids consequent in natural GnRH agonists. Their resistance to degeneration makes the pituitary gland into

**3. Hormonal medical therapy 3.1 Oral contraceptive pill (OCP)** 

days could be advised.

**3.2 Progestins** 

(Yisa etal,2005).

**3.3 Gonadotropin-releasing hormone agonists** 

the latest Cochrane review doesn't show significant effective role of these drugs in patients with endometriosis (Davis etal, 2007).

### **2.2 Cytokines inhibitors**

Research in this field is still in primary stages. In animal experiments, cytokines antagonist agents like recombinant human tumor necrotizing factor alpha (TNF-α) binding protein could inhibit the progress of endometriotic implants and formation of their adhesion (Barrier etal,2004;D'Hooghe etal,2006). Etanercept (ETA) as a TNF antagonist could decrease the volume of peritoneal fluid and proliferation of lesions in endometriotic rats (Zulfikaroglu etal,2011). In a novel study, has been found that TNF could activate estrogen receptor α (ERα); therefore co-administration of a pure ER antagonist with TNF inhibitor could be a more efficacious therapeutic method than usage of one agent, separately (Gori etal,2011).

#### **2.3 New anti inflammatores**

In cases with persistent non responsive symptom to NSAIDs, other inflammatores like leukotrienes could be inhibited (Abu etal, 2000). In one new study, leukotriene receptor antagonist has been shown to have a significant effect in reduction of stromal proliferation in endometriotic implants (Ihara etal, 2004).

#### **2.4 Immuno modulators**

Pentoxiphylline administration in human, like a leukotriene receptor antagonist, had promising results in patients with endometriosis. Although it is famous as a vasodilator agent and increase tissue oxygenation in some disease; but could change the immune cell function by inhibition of cytokine and TNF-α secretion. Although in a Cochran review in year 2009, there were not shown enough evidence to support any differences in pregnancy rate in treated patients in comparison with placebo (Lu etal,2009); but in a new report, Vascular endothelial growth factor (VEGF)-C suggested to be an effective factor for significant reduction in endometriotic implants after Pentoxiphylline administration (Vlahos etal,2010).

Also, other immuno modulators like etanercept (ETA) had promising reductive effect equally to letrozole in early investigation (Ceyhan etal ,2011).

#### **2.5 Alternative medicine**

In a 16 weeks prospective clinical trial, Chinese herbal medicine (CHM) decoctions have been disclosed hopeful reduction in patient's symptoms especially with dysmenorrhea complaint rather than placebo (Flower etal, 2011). According to Cochrane review, CHM have been shown equal results in comparison with gestrinone with lesser side effects; beside that, the combination of oral CMH administration with a CMH enema appear better clinical outcomes (Flower etal, 2009).

As well, there are some published studies about the effectiveness of acupuncture in abdominal pain and significantly in dysmenorrhea relief (M.Chen etal ,2010 ; Rubi-Klein etal,2010). In another clinical trial, abdominal acupuncture causing decrease in CA125 level in endometriotic patients (Xiang etal, 2011).

the latest Cochrane review doesn't show significant effective role of these drugs in patients

Research in this field is still in primary stages. In animal experiments, cytokines antagonist agents like recombinant human tumor necrotizing factor alpha (TNF-α) binding protein could inhibit the progress of endometriotic implants and formation of their adhesion (Barrier etal,2004;D'Hooghe etal,2006). Etanercept (ETA) as a TNF antagonist could decrease the volume of peritoneal fluid and proliferation of lesions in endometriotic rats (Zulfikaroglu etal,2011). In a novel study, has been found that TNF could activate estrogen receptor α (ERα); therefore co-administration of a pure ER antagonist with TNF inhibitor could be a more

In cases with persistent non responsive symptom to NSAIDs, other inflammatores like leukotrienes could be inhibited (Abu etal, 2000). In one new study, leukotriene receptor antagonist has been shown to have a significant effect in reduction of stromal proliferation

Pentoxiphylline administration in human, like a leukotriene receptor antagonist, had promising results in patients with endometriosis. Although it is famous as a vasodilator agent and increase tissue oxygenation in some disease; but could change the immune cell function by inhibition of cytokine and TNF-α secretion. Although in a Cochran review in year 2009, there were not shown enough evidence to support any differences in pregnancy rate in treated patients in comparison with placebo (Lu etal,2009); but in a new report, Vascular endothelial growth factor (VEGF)-C suggested to be an effective factor for significant reduction in endometriotic implants after Pentoxiphylline administration (Vlahos etal,2010). Also, other immuno modulators like etanercept (ETA) had promising reductive effect

In a 16 weeks prospective clinical trial, Chinese herbal medicine (CHM) decoctions have been disclosed hopeful reduction in patient's symptoms especially with dysmenorrhea complaint rather than placebo (Flower etal, 2011). According to Cochrane review, CHM have been shown equal results in comparison with gestrinone with lesser side effects; beside that, the combination of oral CMH administration with a CMH enema appear better clinical

As well, there are some published studies about the effectiveness of acupuncture in abdominal pain and significantly in dysmenorrhea relief (M.Chen etal ,2010 ; Rubi-Klein etal,2010). In another clinical trial, abdominal acupuncture causing decrease in CA125 level

efficacious therapeutic method than usage of one agent, separately (Gori etal,2011).

with endometriosis (Davis etal, 2007).

**2.2 Cytokines inhibitors** 

**2.3 New anti inflammatores** 

**2.4 Immuno modulators** 

**2.5 Alternative medicine** 

outcomes (Flower etal, 2009).

in endometriotic patients (Xiang etal, 2011).

in endometriotic implants (Ihara etal, 2004).

equally to letrozole in early investigation (Ceyhan etal ,2011).
