**5. Potential therapeutic perspectives to restore the estrogen-progesterone receptors balance in endometriosis**

The dysregulation of ER and PR in endometrial glandular epithelium and stroma is for sure a pathological mechanism involved in eutopic and ectopic endometrium in women suffering of endometriosis, a disease with onset during embryofetal life, and long time duration, sometimes up to death. The prevention and the attemps to maintain or restore the ERα/ERβ, and PR-A/PR-B through their normal genes is one of new potential contemporary therapeutic options.

## **5.1 Genetic/epigenetic interventions in dysregulated endometrial progesterone responses in endometriosis**

Progesterone resistance in endometriosis has genetic causes as PRs gene polymorphisms, altered microRNA expression, and epigenetic changes of PRs and their targets. A consequence of impaired progesterone action is that hormonal therapy is rendered ineffective for a subset of women with endometriosis. Environmental toxins as dioxin may play a role in the genesis of endometriosis by permitting an inflammatory milieu.

## *5.1.1 Progesterone responsive genes methylation: a cause of a dysregulated progesterone response*

The studies at Yale University, New Haven, Connecticut (USA) using RT-qPCR for assessment of endometrial genes in mice induced endometriosis compared to normal mice [190] have demonstrated the silencing or inhibition of P4 target HOX genes (HOXA 10/HOXA 11, known also as genes of receptivity) by promoter hypermethylation - an epigenetic mechanism, which favorizes lack of menstrual cycle variation of PRs distribution, which is proper in normal menstruated women, and this is appreciated as a partial explanation for the refractoriness of some endometriotic lesions to progesterone/progestin therapy [7, 191]. Altered PRs expression or diminished activity may lead to attenuated or dysregulated P4 response in ectopic endometrium, and decreased expression of P4 responsive genes including *HOX genes* in the eutopic endometrium. Cakmak and Taylor [191] and Lee et al. [190] concluded that normal endometrium placed in an ectopic location, in order to create experimental endometriosis led to characteristic changes in gene expression of eutopic endometrium, fact that was previously observed regrading stromal stem cells migration to ectopic sites, without this genetic/epigenetic explanation, and it was controverted. These data were suggestive for the existence of a signal

conduction pathway from endometriosis that alters endometrial gene expression through altered *Pgr* signaling and epigenetic programming. The relatively permanent nature of methylation may explain the widespread failure of HT [7]. One discusses about promoters methylation, being controversies if both PRs promoters are methylated, discovering only PR-B methylation, not PR-A [39] or both PRs promoters [192] or DNA methylation of the CG- islands in *PR* promoter, and its gene *HOXA 10* [114] as there are controversions regarding ERs genes (*ESR-1* and *ESR-2*), being hypomethylated CpG island at the *ESR2* promoter region,- involved in primary mechanism responsible for differential expression of *ESR2*, discovered to be increased in ectopic and eutopic endometria [40] while other study from Brazil [192] denies their methylation in eutopic and ectopic endometria.

### *5.1.2 DNA methylation inhibitor: a new therapeutic perspective/challenge to restore PR-mediated signaling molecules in endometriosis*

The women's ectopic and eutopic endometrial progressive loss of PRs and ERα/ PR-mediated signaling in the developing ectopic lesions during 7 to 12 years from histologic disease's onset to clinical symptoms/signs permits to health care providers to intervene in the epigenetic regulation therapeutic control.

The animal studies at the University of Illinois at Urbana-Champaign (USA) [114] have shown that a DNA methyltransferase (DNMT) inhibitor, such as Decitabine (DAC, 5-aza-2′-deoxycytidine), an analogue of deoxycytidine that can incorporate into DNA strands and cause DNA demethylation [193] compared to vehicle administration in immunocompetent mice induced endometriosis, treated also with E2 had alleviated lesion growth, and increased expressions of PR protein, and miRNA corresponding to *Esr1*, *Pgr*, *Hand2*, and *Hoxa10*, (P4 target), but not for *Ccl5* and *Ptgs2* in the eutopic endometrium and ectopic sites. The results of the study enable the authors to review the involvement of estrogens and progesterone in eutopic and ectopic endometrium, the epigenetic regulation including DNA methylation, the fact that ERα and ERβ *(*ESR1 and ESR2), PRs (PRA and B), as well as PR-targets *Hoxa10*, *Gata2/6*, and *Hand2* are susceptible to DNA methyltransferases, leading to an aberrant expression of these molecules in endometriosis.

Early studies showed that the promoter sequences of ERα and ERβ (*(*ESR1 and ESR2), PRs (PR-A and B), as well as PR-targets *Hoxa10*, *Gata2/6*, and *Hand2* are susceptible to DNA methyl transferases, leading to an aberrant expression of these molecules in endometrial diseases [194] and loss of PR-mediated signaling during disease progression contributes to the increased susceptibility to P4 resistance in ill women. Li et al. [114] accepted the proposed role of inflammation to provoke widespread changes in the genes and chromatin landscape of lesions, because their analyses showed that DNA methylation in PRs and *Hoxa10* promoters was enhanced in the ectopic lesions in comparison to the normal endometrium, and inhibition of genome-wide DNA methylation in female mice restrained lesion expansion and partially restored target gene expression.

## **6. Conclusions**

Endometriosis is a chronic disease, with possible onset in embryonic life, latency in childehood, reactivation from the menarche, with clinical symptoms and signs difficult to be early accurate assessed during reproductive years. Endometriosis has a progressive evolution, which drives through tissue intrinsic properties to increase lesions size and number, and to functional damages of original eutopic endometrium. The cascade of dysregulations in chromatin machinery is difficult

#### *Potential Therapeutic Options and Perspectives for Alleviation of Endometrial Estrogen… DOI: http://dx.doi.org/10.5772/intechopen.100039*

to be stopped by hormone therapy and surgery (associated in different strategies), when the abnormal signaling of steroid hormones has started: endometrial estrogen dominance and progesterone attenuate response up to progesterone resistance, because their genes epigenetic disorders. The 7–12 years delay in diagnosis and proper therapy drives to accentuation of chronic pelvic pains, dyspareunia, dyschezia, infertility/subfertility.

The best therapy is to avoid the dysregulation of steroid hormones signaling, induced initially in ectopic and later in eutopic endometrial stroma and glands, to maintain or to restore the estrogen/progesterone receptors natural balance, which may be possible when an early intervention, from the menarche. One may discuss about timing in starting HT in adolescent girls with family history of endometriosis, precocious dysmenorrheal, menorrhagia, abundant blood and clots loss, favorising menstrual blood reflux.

First line therapy is progesterone/progestins, working in prevention of estrogen dominance and progesterone dysregulated signals, and can maintain their positive effects, when it is early administrated, as animal models have shown. One must recommend this first line therapy, for a long time duration, with a single drug (micronized progesterone, or dienogest, a new progestin) or combined with a synthetic/natural estrogen in COCs, in cyclic or in continuous/extended regimens up to response failure, with the advice to avoid drug discontinuation. Vaginal route for micronized progesterone, IUD with progesterone/levonorgestrel may work better for alleviation of estrogen dominance and progesterone resistance.

GnRH agonists/antagonists- second line therapy, are active in correcting the steroid imbalance, but less than our expectances, even with the new oral molecules (as elagolix), or combination of molecules [GnRH antagonists (relugolix or elagolix) plus an estrogen, or plus an estrogen and a progestin], which were proposed to avoid or to reduce add back therapy. The most recent studied molecule of elagolix may be used no longer than 24 months, because a longer administration may impose add back therapy.

Aromatase inhibitors are also second line therapy, recommended in selected patients for refractory endometriosis, with chronic pelvic pains. Letrozole combination to norethindrone acetate is better than the progestin alone in correcting estrogen dominance, and progesterone resistance.

The new therapeutic perspectives regarding the combination of ER agonists with co-activators, and DNA methylation inhibitors are still in studies at high level technology laboratories, not for current medical use.
