**4.2 New therapeutic strategies to restore estrogen-progesterone endometrial balance in endometriosis. Selective estrogen receptor modulators (SERMs). Selective progesterone receptor modulators (SPRMs)**

Medical literature presents under the name of selective estrogen receptors modulators (SERMs) a relative new cathegory of drugs aimed to target downregulation of E2 signaling, by a direct binding to ERs in a tissue specific manner [91]. The studies on rat induced endometriosis [157] have shown the reduction of endometriotic lesions by down-regulation of ESR1 and cell proliferation by bazedoxifene or by raloxifene, but in a RCT on administration of raloxifene (180 mg/ day) after laparoscopically apparent complete excision of ectopic lesions, it was recorded a shortly time for chronic pain relapse with raloxifene vs. *placebo*, but without recurrence of endometriotic lesions at the second laparoscopy [158] and these results have reduced the enthusiasm for first and second generation of SERMs in endometriosis. The third generation of SERMs administration - basedeoxifene, reduced glands size and number of ectopic sites in mice [159].

The selective progesterone receptor modulators (SPRMs) are known since long time, with the antiprogesterone representative RU 436 or mifepristone. SPRMs were proposed to treat unresponsive cases to progestin treatment, due to progesterone resistance dilemma [160] connected to their direct interaction to progesterone receptors, in order to reduce estrogen- induced cells proliferation and prostaglandins production [161]. Two old multicentres trials on mifepristone showed its efficacy in the endometriosis chronic pain control, with lesions size reduction, although results are mixed [162, 163].

Ulipristal acetate suppressed ectopic endometrium induced in mice, with slow reappearance after discontinuation [100]. After many discussions on the promising evidence of inhibiting human endometrial cell proliferation *in vivo* [164] and on the so-called progesterone receptor modulator-associated endometrial changes (PAEC) recorded after 6 months of therapy, which is reversible after ulipristal discontinuation [164] the liver life threatening complications induced the discontinuation of the study on endometriosis effects [165].

Per global these so called "new" classes of molecules with selective receptors of steroid hormones modulation objectives did not covered the expections in endometriosis, according to women pathologic condition progressively induced on their steroid hormones receptors dysregulation/loss.

## **4.3 New potential therapeutic perspectives: A combination therapy using agonist of ERβ and the SRC-1 isoform as the next generation of endometriosis therapy to restore estrogen-progesterone signaling balance**

Long duration of systemic hypoestrogenism may affect brain, heart, and bones, in young women, and for non responders to first line therapy mentionned above, long term medication with GnRH agonists/ antagonists or aromatase inhibitors cannot be recommended, fact that imposed more researches to try to improve estrogen dominance/progesterone resistance, to stop ectopic tissue growth and disease stage progression with chronic pelvic pains, and infertility. These aims were objectives at the Bayllor College of Medicine, Houston (USA) where it was proposed a combination therapy using an agonist of ER β and the steroid receptor coactivator-1 (SRC 1) isoform as the next generation of endometriosis therapy – Han et al. [44] (**Figure 2**). *Potential Therapeutic Options and Perspectives for Alleviation of Endometrial Estrogen… DOI: http://dx.doi.org/10.5772/intechopen.100039*

#### **Figure 2.**

*Hypothesis of Bulun SE, et al. on hypomethylation of ER*β *promoter in endometriotic stromal cells vs. hypermethylation, which suppresses the promoter expression in normal endometrium by blocking transcriptional complex including co-activators of ER-* β *(adapted from Bulun et al. [45]: open acces).*

The combination of ERβ- selective agonist and SRC-1 is based on the significant supressive effect of PHTPP on ectopic lesion growth by inhibiting ERβ activity in mice induced endometriosis [166] associated to minimum side effects on ERα, without influences on eutopic endometrium or negative influences on mice fertility. SRC-1 is considered a PR co-activator, and indirectly through it, ERβ may impair PR-mediated signaling in the ectopic lesions, because actually it is no evidence available to show that PR could potentially interact directly with ERβ [167]. These drivers combination allows marked suppression of ectopic lesion growth compared with either individual agents alone, both demonstrating essential roles in early stages of disease pathogenesis [168] specially on apoptosis modulation and inflammation reduction.

#### **4.4 Potential therapeutic options for estrogen dominance control**

Several medical treatments for endometriosis directly aim to reduce E2 production or action in order to mitigate E2 dominant conditions, and actually one discusses GhRh agonists, and the new class of GhRh antagonists. These therapies are efficient in cases wishing to conceive, and for the control of chronic pelvic pains- menstrual and non-menstrual [169] but associated hypoestrogenism is cause of many health concerns, requiring hormone "add-back" for long term use [91]. Numerous studies included in the *Cochrane Data Base Systematic Review* (2003) [170] revealed since long time that these effects limit the duration of treatment, which cannot be administered without "add back"/hormone-replacement therapy [171] and treatment cannot be dose-adjusted to alleviate the side effects - Practice Committee of the American Society for Reproductive Medicine (2014) [172].

The recent history of HT for estrogen dominance and progesterone resistance in endometriosis shows that the "old" injectable depot MPA, which can decrease ESR1 and ESR2 while increasing PR-A and PR-B in the eutopic and ectopic endometria [173] has equivalent efficacy to leuprolide- a GnRH agonist, in reducing pain, but with less adverse hypoestrogenic effects on bone density [174].

#### *4.4.1 GnRH agonists. GnRH antagonists*

Injectable GnRH agonists (leuprolide, diferelin, nafarelin) are normally secondline treatments. Which decrease hormone levels by down-regulating the pituitary through negative feedback mechanisms [91] and indirectly they favor an endometrial complete silenced hormonal milieu, on the bases of estrogen dominance concept. GnRH agonists have been shown to be effective in reducing endometriosisrelated pain [175] with adverse effects – hot flushes, bone mineral density loss, or coronary heart disease, headaches due to a hypoestrogenic state, requiring hormone "add-back" [91]. It was reported a mean percent decrease from baseline in bone mineral density at the lumbar spine of 3.2% at 6 months, and of 6.3% at 12 months after leuprolide alone, and these side effects were associated with rates of discontinuation by 6% because hot flushed, and 8% because of emotional changes [171].

GnRH antagonists, known since long time [176] were in last 10 years under investigation for endometriosis treatment in USA, and Europe according to their capacity to downregulate gonadotropins, without flare-ups like GnRH agonists because they rapidly and directly compete for GnRH receptors [177] and the oral administration is another benefit. Their mechanism of action is different to that of GnRH agonists. After an initial stimulatory phase desensitize GnRH receptors in the pituitary, causing a subsequently depletion of pituitary gonadotropins and full suppression of E2 to levels that are equivalent to those associated with bilateral oophorectomy [178].

Based on Barbieri RL (1992)" estrogen threshold hypothesis" [179] the 2 large multicenters RCTs (Australia, Brazil, Canada, New Zeeland, Poland, USA) [177] have concluded that the new oral Elagolix, a nonpeptide GnRH antagonist, in 2 different doses (one with Elagolix 150 mg/day, and the other RCT with Elagolix 100 mg twice/day) significantly lower scores for dysmenorrhea and non-menstrual pelvic pain than *placebo* after 3 and respectively 6 months of treatment, and dyspareunia at 3 months, with significantly better results in cases on 200 mg/day with respect to the use of rescue analgesic agents at 3 months and 6 months, dyspareunia at 3 months, and rescue opioid use at 3 months less than did those receiving *placebo*. The dysmenorrhea control was better than that of non-menstrual pelvic pains, dysmenorrhea is mostly dependent on cyclic changes in ovarian hormones, whereas the mechanism of non-menstrual pelvic pain are considered more complex [180]. The results allowed the researchers to consider that complete estrogen supression may not be needed to controll endometriosis- associated pain, and estrogen may be adjusted to a level that is adequate to control pain with minimum hypoestrogenic effects (hot flushes, bone mineral density, lipid levels), more frequently claimed in the higher dosage, similar to those induced by GnRH agonists. Elagolix was associated with an antiproliferative effect at each dose, and with endometrial atrophy at higher dose, which was consistent with decreases in endometrial thickness at that dose, but there were considered some limits of the study, as time since endometriosis first surgical diagnosis (in between 10 years), short duration (6 months) of drugs administration. Elagolix did not completely suppress ovulation at either of the two doses [181] being recorded pregnancies, even if patients were recommended to use non – hormonal contraceptive methods during trials. Presently one waits the published results of a phase 3 multicenters RCT in Eastern European countries on an daily oral combination of GnRH antagonist (relugolix) with low doses of estradiol and norethindrone acetate regarding endometrial histology, and endometriosis associated chronic pain, and side effects in comparison to the 4 weeks injectable leuprolide.

#### *4.4.2 Aromatase inhibitors*

Aromatase inhibitors (AI), anastrozole and letrozole - the most known derivates, were destinated for control of local E2 levels in many pathologies, and in endometriosis they induce regression of peritoneal lesion size, in a higher degree than MPA [182] by reducing androgen aromatization into estrogens, both in adipose tissue and within endometriotic sites. These drugs are inhibiting endometrial progenitor cells migration to ectopic sites [183], and by increasing apoptosis, and diminishing endometrial VEGF and PGE2 in a mouse model [184] they reduce chronic pelvic pains. AI have significant adverse effects like irregular bleeding, and joint pains [185].

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

AI action is explained by the promotion of pituitary gonadotropin hormones release, with consequent ovarian stimulation; therefore, they must be combined with a progestin or other method of gonadotropin inhibition to treat endometriosis in premenopausal women [186]. There was compared the association of letrozole (2,5 mg/day) to NETA (2,5 mg/day) vs. NETA (2,5 mg/day) alone, and the Italian open-label study proved a better control for pain and dyspareunia of the drugs association in rectovaginal endometriosis [187] with a better sizes reduction of rectovaginal nodules [188] and of endometrotic ovarian cysts [189]. The effect of the combination of a progestin to an AI is not lasting after termination of HT, so Reis et al. [7] in their published review on progesterone ligands consider letrozole as a second therapeutic- line for selected patients, who fail to respond to first line HT- progesterone/progestins.
