**2.3 E2 and P4 endometriosis**

The ovarian steroid hormones play also a central role in pathogenesis of several uterine disorders, including endometriosis, which is characterized by the presence of endometrial tissue outside the uterine cavity like the peritoneum and ovary. It has been shown that both

The Tissue Specific Role

al., 2002).

endometrium.

**3.2 Selective ER and PR modulators** 

of Estrogen and Progesterone in Human Endometrium and Mammary Gland 43

Third of female malignancies are hormone dependent in their growth. Most prominent leading death causing factors for women under age of 50 are breast cancer and also various cancers of reproductive system. Many factors are involved in the development of breast cancer, including genetics, lifestyle, diet, endogenous hormone status and environment. Demographic risk factors for breast cancer are early age of menarche, nulliparity, late fullterm pregnancy, higher social class and increasing age. Known factors with protective effects on breast cancer development are early full-term pregnancy, increasing number of births, longer periods of anovulation and more physical activity (Bernstein et al., 1994). The incidence of this lethal cancer has steadily increased during the last centuries in part due to the better and more widespread screening procedures. Increased ERα expression is one of the earliest changes occurring in the tumorigenic process and is associated with uncontrolled proliferation of the breast tissue (Khan et al., 1994). Some data is showing that ERβ could negatively modulate the effects of ERα but the prognosis for endocrine therapy are still under the question because of the somehow contradictory outcomes (Roger et al., 2001; Speirs et al., 2002). Similarly PR isoform ratio also seems to have a role in breast tumorigenesis as the ration of PRA and PRB has been altered with PRA prevalence (Mote et

Currently, only the expression level of ERα is measured for clinical decision-making and treatment of breast cancer patients as a favourable prognosis in primary tumours. Still, only 50% of ERα-positive tumours respond well to hormonal therapy. Large research programs are dedicated to search for better and more specific clinical breast cancer markers. The significance of ERβ status is still controversial and further analysis of the role it plays in the pathogenesis of breast cancer is required. As more experimental information on E2 mediated signalling accumulates, new possibilities emerge for breast cancer therapy.

Selective ER modulators (SERMs) function through ERs, acting as agonists or antagonists of E2 depending on the target tissue and modulate the signal transduction pathway to E2 responsive genes. The implementation of SERMs in clinical aspects is wide. They are used to treat or prevent breast cancer and osteoporosis, to cure ovulatory dysfunction in women but also for contraceptive purposes. SERMs have an ability to differently regulate many ERregulated genes (Berrodin et al., 2009; Chang et al., 2010). In general, most SERMs have E2 agonist activity in bone and antagonist activity in the breast, while the activity in the uterus varies among the molecules. The tissue specificity depends on various co-activators (CoA) and co-repressors (CoR) expressed and recruited in different tissues (Riggs et al., 2003). E2 binds to either ERα or ERβ and subsequently binds CoA molecules required to form a transcription complex at EREs located in the promoter region of estrogen-responsive genes. The antiestrogenic action of a SERM results from the inappropriate folding of an ERα or ERβ complex that either cannot recruit CoA molecules or instead recruits CoR molecules. This programmed change in conformation produces antiestrogen action at specific sites like the breast, but estrogen-like effects in the uterus if an excess of CoA molecules is present. SERM–ER complexes may initiate gene transcription to produce an estrogen-like effect, by forming a protein–protein interaction at fos/jun that activates AP-1 sites (Jordan et al., 2001) (Figure 4). Although widely used and with many beneficial effects in treating breast cancer SERMs still battle with several side effects where most common is the stimulation of the

eutopic and ectopic endometrial tissues expresses ERs and PRs and they respond to ovarian steroid hormones but the predominance of ERα and PRA receptors have been described in cases of ectopic lesions (Matsuzaki et al., 2001; Attia et al., 2000). Despite the obvious importance of E2/P4 in the development of the endometriosis, the exact aetiology and pathogenesis of it are still unclear. It is predicted that in general endometriosis could affect about 10% of women of reproductive age and up to 25-50% of women seeking infertility treatment. There is still uncertainty whether the decreased fertility is related to reduction of the oocyte/embryo quality or dysregulation of the endometrium (Kim et al., 2007). Aberrant gene expression in endometrium which is suboptimal for implanting blastocyst has been shown by several studies in cases of endometriosis (Giudice et al., 2002; Kao et al., 2003).

Even though endometriosis has been characterized as E2-dependent gynaecological disease, where E2 favours the growth of the tissue, the dysregulation of the P4 response on the molecular level is suggested in endometriosis. It has been noticed that endometriotic tissue does not respond to P4 as normal endometrium does. Altered PR expression or diminished activity predictably results in differential gene expression compared to eutopic tissue (Cakmak et al., 2010). For example, altered P4 signalling can cause unpaired regulation of *HOXA 11, HOXA12* genes in ectopic tissue which are expressed in high levels during the IW in normal tissue (Cakmak et al., 2010). The up-regulation of *HOXA10* and *HOXA11*  expression fails to occur in women with endometriosis (Taylor et al., 1999). Recent studies looking for functional miRNA-s have shown up-regulation of miR-21 in eutopic endometrium of women with versus without endometriosis (Luo et al., 2010; Aghajanova et al., 2011).

Hopefully further studies in the future help us understand the molecular mechanisms, which are responsible for the development of endometriosis.
