*4.1.2 Timing progesterone/progestins for preventing progesterone attenuance and progesterone resistance in endometriosis*

The discussion on administration of progesterone from early ages of reproductive period, just to permit P4 to stop endometriosis progression, inflammation, and angiogenesis, by maintainance of ERs, PRs normal ratios in epithelial glands and stroma, is supported by Li et al. study [114] at University of Illinois at Urbana-Champaign, (USA). Endometriosis was induced in two immunocompetent mice groups, differently maintained afterwards: one group with E2, and the second group with E2 and P4 subcutaneously, at every 4 days beginning at 4 days before lesion induction (pre- P4 treatment). The endometriosis-like islands were very quickly developed, with different numbers, aspects and sizes according to steroids administrated- after E2 alone there were yellow, more numerous, larger, with abundant blood vessels and extensive adhesions; after E2 plus P4 were white, smaller, non-vascular, with loose attachment. The microscopy (H&E, special biomarkers, IHC for ER, PR, their genes) have shown marked differences regarding mitotic activity (Ki-67 reduction), glandular secretion, endothelial cells and angiogenesis (CD31 increased when was added P4 before induced endometriosis). Another peculiar aspect in the treated group with E2 plus P4 are the inflammatory response changes - first an increase, and later a reduction of inflammatory cells, and changes of their type in endometriosis-like tissues, with similarities between groups in the first 16 days, and a dramatically changed aspect of inflammation after 24 days from induced endometriosis, such as suppressed production of pro-inflammatory cytokines, and infiltration of immune cells in ectopic sites. The authors debated the P4 action to alleviate lesion outgrowth and to maintain ERα and PR expression


**Table 1.**

*Progesterone alleviates endometriosis, induced in the peritoneal cavities of femele immunecompetent mouse, maintained with estrogen if administered before illness induction (from Li et al. [114]).*

<sup>•</sup> P4 restricts expansion of the ectopic lesions by inhibiting endometrial cell proliferation, and neovascularization

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

when P4 is administrated before lesion induction. The use of RT- qPCR permited the endometrial genes assessment in eutopic and ectopic endometria, showing a progressive down-regulation of miRNA expression corresponding to ESR1, PRs and PR-stromal targets *Hand2* and *Hoxa-10* with time of disease progression, and in contrast a gradually increase of ESR2 miRNA, parallel to increased expression of ESR1, PRs, and *HOXA 10* in ectopic lesions, while *Hand2* expression remained suppressed when P4 was administered before lesion induction (PreP4). The P4 inhibitory effect was not observerd when P4 was started at 4 days after endometriosis induction (Post-P4). The study results clearly indicate that the loss of PR-mediated signaling components is a major causal factor for the P4 resistance existing in mice with endometriosis. The conclusion is that progesterone supplementation from early moments of disease, when PRs are still present can preserve steroid responsiveness and ameliorate E2-dependent disease progression, but when at later stage, P4 supplementation has minimum effects, because of PRs absence. The hope is that if PRs women's loss is progressive after disease onset, the add of P4/progestins may action with the wanted effects.
