**4. Potential therapeutic options to maintain/restore endometrial normal estrogen-progesterone signaling in endometriosis**

Presently pharmacotherapy mainly with hormones (Hormone Therapy- HT) and surgery are two cornerstones in endometriosis management. Surgery with histological confirmation of ectopic endometrial glands and stroma remains the gold standard for diagnosis [75, 76] surgery being generally reserved for patients who fail medical therapy, or who desire pregnancy, being usually performed by laparoscopy [77, 78]. Surgery is able to eliminate visible endometriotic lesions, without the cure of the disease [79], and majority of drugs are symptomatic, not cytoreductive [80]. Yet it is not known if surgery itself may be incomplete (*i.e.*, microscopic disease)

or if other factors, such as aberrant PRs expression of the eutopic endometrium influences recurrence [60] connected to the eutopic endimetrium transcriptome changes compared to non-ill women, indicating abnormalities that predispose to new implants in extrauterine locations after surgical excision of ectopic lesions [81]. Recurrence rate after surgery or medication discontinuation was recorded up to 45% after 5 years [82] and recently one discusses the translation from adjuvant therapy to tertiary endometriosis prevention in postoperative medical care [83]. The moment of medical therapy associated to surgery- before, after, or both before and after surgery is much analyzed, to maximize treatment response, but literature data is still inconclusive [84]. The HT goal is to induce atrophy of endometriotic lesions, even if one missis the ability to predict which medication each individual patient will respond to, being many attempts to find one or more predictive markers [85] to score HT, as it is the immunohistochemical Histo (H) -score on the PRs status, and CYP19A1 expression for the response to progestins, respectively for the need to block estrogen signaling [60]. The high H-score for PRs was proposed to be >80 (associated with 100% positive predictive value), and the low H-score ≤ 5 (associated to 94% negative predictive value), with some authors' comments regarding H-score usage: the score is useful for ectopic endometrium response to progestin- based therapy, not for eutopic endometrium, because the lack of score's correlation to eutopic endometrium. It is recommend to score PRs in the excised ectopic tissues, and to determine the reason for progesterone/progestins/COCs failure. When adhesions/fibrosis are predominant it is sure the non-response to HT, but some PRs expression may indicate an insufficient dosage of progestin or noncompliance with therapy (*i.e.*, inability to tolerate side effects), and for cases with low H-score, patients being PR resistant, it is advised to avoid progestins after surgery in favor of GnRH agonists or GnRH antagonists [86, 87], danazol- rarely used actually, or aromatase inhibitors.

Actual medical therapies allow suppression of endometriotic lesions, women require long term treatment [79] to maintain the benefits, to avoid recurrences, being recognized high rate relapse even after surgery. After surgery one must continue HT with contraceptive pills, or IUD [88] with the aim to preserve ovarian follicles reserve, and because ovarian aging, to try spontaneous pregnancy or ART.

Individual genetic characteristics can affect the bioavailability and pharmacodynamics of HT, mainly estrogen dominance and P4 resistance/attenuance, and, hence, explain part of the variability in the therapeutic response, as it is the polymorphism of CYP3A4/5 involved in levonorgestrel metabolism [89].

One can respond to therapeutic wishes by timing progesterone/progestins administration, and by moving from pure hormonal therapy to drug combination, or to novel molecules capable to restore the various homeostatic disrupted mechamnisms by disease. A number of potential therapeutics are currently in pre-clinical or early clinical studies, fact which may alter further treatment strategies.

#### **4.1 Progesterone/progestins therapy**

Kistner [90] was first who postulated that decidualisation observed during pregnancy might cause necrosis, and the consequent elimination of superficial ectopic implants, and this was the logical reasoning for progesterone recommendation, and use to control endometriosis. During pregnancy on assists at ovarian functions suppression, fact that is mimicised by HT in endometriosis [91]. After Kistner RW first initiave in the years 1960, there were used progestins, which are inducing a pseudo-pregnancy endometrial aspect or endometrial atrophy at microscopy [92]. The progestins are synthetic different derivates, such as C-21 progesterone derivates (medroxyprogesterone acetate, MPA, and depot MPA, and dydrogesterone,

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

(DYD- a semisyntethic progesterone derivate), or C-19 nortestosterone derivates (levonorgestrel, norethisterone, lynestrenol, desogestrel, and dienogest), or the 19-norprogesterone derivates without androgenic activity; nomegestrol acetate – (NOMAC) has a similar anti-gonadotropic activity compared to the 19-nortestosterone derivates with androgenic activity, norethisterone acetate (NETA) [93] and a separate class with drospirenone, the unique progestin [94]. The COCs with the synthetic ethinyl-estradiol (20, 30 μg/pill) plus one of the previously mentioned progestins represent a very important cathegory in the control of eutopic and ectopic endometria from intrinsic abnormal steroids signaling [95]. One must keep in mind the Japanese oppinion [96] that concurrent estrogen action is essential for maximal progestin effect in COC, fact controverted by some studies regarding patients satisfaction on pain alleviation in endometriosis, explained by summerizing endogenous estrogen local levels in ectopic endometrium to that of pills [97] but estrogen priming may be necessary to induce PR in endometriotic lesions [96, 98] as progesterone usually actions on estrogen primed tissue. Progesterone and progestins, alone or in association to a synthetic estrogen are considered first line therapy in endometriosis. The positive response to progestins alone or combined estrogen- progestins may induce only partial improvement, the ectopic sites are not eliminated or some patients do not respond at all [99] being recognized only the quiescence of lesions, at best [100] and when first line therapy fails – in one- third of women because progesterone resistance [79] or it is contraindicated, or it is not tolerated one recommends Gonadotropin-Releasing Hormone (GnRH) agonists, GnRH antagonists, and aromatase inhibitors being used in cases refractory to other therapy. Up to 2021 it was published a single RCT on COCs in endometriosis [101] as Donnez and Dolman [79] mentionned in the last European review. It is described a statistically significant, though modest, improvement in dysmenorrhea with OCPs given for four months compared to *placebo*, and a lack of any beneficial effect of OCPs on non-menstrual pelvic pain and dyspareunia, being appreciated the studies failure to report data on their efficacy according to lesion phenotype [102, 103].

Patients present variable responses to progesterone/progestins, according to their pharmakinetics, to their capacities to reacts to medication (genes, receptors for E2, P4), to metabolize progesterone/progestins connected to their levels of N-Acetyl transferases, associated to drug kinetics control by acetylating and converting active forms into inactive metabolites, to their cytochrome P450 3A (CYP3A) system- one of the most known pathway in steroid hormones metabolism,and P450 3A polymorphism is not precisely known in endometrial patgology [89].

#### *4.1.1 "Old" hormone therapies still active in endometriosis*

During the long time of progestins usage it was reported a good rate of patient adherence and satisfaction [104, 105]. There are few direct comparisons between different types of progestins in endometriosis clinical studies, with the scarce evidence suggesting that when given by the same route and the same regimen, the effectiveness may be similar [7]. By binding to PRs, progesterone/the synthetic compounds, administrated orally or by non conventional routes (vaginal [106], intrauterine [107]) induce inhibition of estrogen synthesis through down regulation of ERs [64] and of steroidogenic enzymes in endometrial stromal cells, either by up regulation of the oxidative 17β-HSD type 2, which transforms E2 to E1 [108], being triggered by retinoic acid [109] or by reduction of 17β-HSD type 1 expression, and activity, − as was proved specially for MPA, DYD, dienogest [108, 110] which induces the inhibition of aromatase expression with a low local estrogen production in immortalized human endometrial epithelial cells [111] with inhibition of eutopic and endometriotic cells proliferation, and reducing cells survival by apoptosis

induction [112] with limitation of local angiogenesis and neurogenesis (proved with the CD31- a neurovascularisation marker), and linking all these mechanisms, the attenuation of the immune-inflammatory response (proved to be more accentuated on new progestins as drospirenone by its effects on inflammatory cytokines - VEGF, and nerve growth factor) [113] so progesterone/progestins change the morphology of endometrium- ectopic and eutopic with reduction of lesion sizes, but with net differences in their response to these drugs, as experimental and clinical studies demonstrated [7, 114], stages III- IV are not responding. Longitudinal assessment of endometrial morphology has demonstrated that the histology aspects are changing in time: initially one registers secretory differentiation, and after several cycles through ERs down- regulation one registers atrophy with tubular glands, weak secretory vacuolation, and stroma low cellular density [115]. Usually one recommends a HT for long term duration, short term therapy being insufficient to obtain the wanted effects, even with dienogest, − which in a short term therapy demonstrated a high frequency of decidualisation and a tendency of inflammation reduction, but it was not able to induce differences comparable to non- treated cases in terms of necrosis, glandular atrophy and angiogenesis [116] (**Table 1**).
