**Abstract**

Endometriosis is a chronic disease, influenced by internal and external environment, with long duration from intrauterine life with acme during childbearing, when it is associated to chronic pelvic pains, and infertility/subfertility. DNA hypermethylation of endometrial promoter PRs *Hox genes* and DNA hypomethylation of promoter ERβ *gene* is a possible explanation of estrogen dominance, progressive loss of progesterone signaling, followed by progesterone resistance in ectopic, and progesterone attenuance in eutopic endometrium, for failure of hormone therapy (HT), repeated recurrences after surgery, cancers after long time evolution. Animal models, human trials demonstrated progesterone (P4) and progestins influences over progression of disease pathological characteristics, associated to endometrial ER, PR aberrant expressions: ERα loss, and abnormal PRB/PRA *ratio*. P4 supplementation before mice induced-endometriosis protected from PRs depletion, action that can be translated in women according to the difference of 7 to 12 years between histologic onset and clinical symptoms/signs, parallel to progressive loss of PRs and PR-mediated signaling in ectopic and eutopic endometria. The animal studies have shown that a DNA methylation inhibitor alleviates lesion growth, and induces PRs target gene expression restoration. Continuous/extended contraceptives, dienogesta new progestin, GnRH agonists/antagonists, aromatase inhibitors, SERM, SPRM, combinated molecules are therapeutic options/perspectives aiming restoration endometrial estrogen-progesterone balance, without disease's cure. HT may be active alone, or surgery associated.

**Keywords:** endometriosis, estrogen dominance, progesterone resistance/attenuance, timing, progesterone/progestins, DNA methylation inhibition
