**3.1 Oral contraceptive pill (OCP)**

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 days could be advised.

#### **3.2 Progestins**

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 (Yisa etal,2005).

#### **3.3 Gonadotropin-releasing hormone agonists**

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

Medical Treatment in Endometriosis 479

therefore they administrate with GnRH agonist or OCPs or progestins. This method could reduce the concern about their disadvantage in prolong usage: bone loss (Ferrero etal

Suppression of cellular immunity and NK cell activity in endometriotic patients has been well known. Also, in stressful situations inhibition of NK cell had been found (Chrousos etal, 2000). Prolactin and cortisol levels in serum are stress indicators. Of course the mechanism of hyper prolactinemia in response to stress isn't so clear, elevated level of serum prolactin had been found in endometriosis like other stressful conditions (Lima etal, 2006, Wang etal, 2009). Interestingly the mean serum prolactin levels are higher in advance stages in endometriotic patients (Gregoriou etal ,1999). Quinagolide as a dopamine receptor 2 agonist by reduction in VEGF receptor (a main factor for angiogenesis) could decrease the size of peritoneal lesions and in some cases could eradicate all of endometriotic implants (Gomez etal, 2011). From another aspect quinagolide, is a valuable option for hyper prolactinemia like other dopamine agonists (bromocriptine or caberguline) (Barlier&Jaquet,2006); therefore this drug could be effectively administrated in

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**4. References** 

**3.7 Prolactin secretion inhibitors** 

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down regulation state and after suppression of FSH and LH production, menstruation and ovulation had been stopped and therefore, low estrogenic environment achieved which inhibits the proliferation in endometriotic implants. Beside initial flare effect, pseudo menopausal situation produce minor side effects like hot flashes, vaginal atrophia and dryness, headache and other vasomotor signs and symptoms (Dlugi etal,1990) which could be managed by add-back therapy, but after 6 or more continues cycles of drug administration, bone mineral density is going to be reduced sometimes in an irreversible manner (Taga etal,1996); but there is an interesting report about ten years usage of GnRH agonist with add-back therapy without any bone mineral loss (Bedaiwy etal,2006). Unlike the progestins and danazole, GnRH agonists had not adverse effects on lipid profile (Burry etal,1989).Several kinds of injectable GnRH agonists and nasal spray form are available with equal efficacy (Prentice etal,2000).
