Progesterone receptor ligands for the treatment of endometriosis: the mechanisms behind therapeutic success and failure

Abstract

BACKGROUND Despite intense research, it remains intriguing why hormonal therapies in general and progestins in particular sometimes fail in endometriosis. OBJECTIVE AND RATIONALE We review here the action mechanisms of progesterone receptor ligands in endometriosis, identify critical differences between the effects of progestins on normal endometrium and endometriosis and envisage pathways to escape drug resistance and improve the therapeutic response of endometriotic lesions to such treatments. SEARCH METHODS We performed a systematic Pubmed search covering articles published since 1958 about the use of progestins, estro-progestins and selective progesterone receptor modulators, to treat endometriosis and its related symptoms. Two reviewers screened the titles and abstracts to select articles for full-text assessment. OUTCOMES Progesterone receptor signalling leads to down-regulation of estrogen receptors and restrains local estradiol production through interference with aromatase and 17 beta-hydroxysteroid dehydrogenase type 1. Progestins inhibit cell proliferation, inflammation, neovascularisation and neurogenesis in endometriosis. However, progesterone receptor expression is reduced and disrupted in endometriotic lesions, with predominance of the less active isoform (PRA) over the full-length, active isoform (PRB), due to epigenetic abnormalities affecting the PGR gene transcription. Oxidative stress is another mechanism involved in progesterone resistance in endometriosis. Among the molecular targets of progesterone in the normal endometrium that resist progestin action in endometriotic cells are the nuclear transcription factor FOXO1, matrix metalloproteinases, the transmembrane gap junction protein connexin 43 and paracrine regulators of estradiol metabolism. Compared to other phenotypes, deep endometriosis appears to be more resistant to size regression upon medical treatments. Individual genetic characteristics can affect the bioavailability and pharmacodynamics of hormonal drugs used to treat endometriosis and, hence, explain part of the variability in the therapeutic response. WIDER IMPLICATIONS Medical treatment of endometriosis needs urgent innovation, which should start by deeper understanding of the disease core features and diverse phenotypes and idiosyncrasies, while moving from pure hormonal treatments to drug combinations or novel molecules capable of restoring the various homeostatic mechanisms disrupted by endometriotic lesions.

Markers of Cellular Proliferation, Apoptosis, Estrogen/Progesterone Receptor Expression and Fibrosis in Selective Progesterone Receptor Modulator (Ulipristal Acetate)-Treated Uterine Fibroids

“…Leiomyoma fibrosis, which affects the accumulation of ECM and indicates the inflammatory nature of these tumors, poses interesting research questions, especially when it remains unclear what effect SPRM treatment has on fibrosis process in myomas and whether the accumulation of fibrosis in leiomyoma can affect the response to this treatment. It has been noticed that effects of SPRM action can depend on several factors, as PR expression in tissue and changes in these receptors are conditioned by different ligands [ 13 ]. The understanding of estrogen receptor (ER) and PR expression in fibroid tissue post-SPRM hormone treatment remains incomplete.…”

Endometriosis and Medical Therapy: From Progestogens to Progesterone Resistance to GnRH Antagonists: A Review

“…As demonstrated in 1995, a progestogen (lynestrenol) was unable to reduce vascularization (evaluated by the capillary–stroma relative surface area) in endometriotic lesions, but a significant decrease was observed after GnRH agonist therapy [ 55 ]. A recent review by Reis et al [ 56 ] also confirms that deep endometriosis appears to be more resistant to regression upon medical treatment. According to the literature, some authors found a substantial volume reduction during OCP and norethisterone acetate (NETA) therapy [ 57 ], but this was not confirmed by other more recent studies [ 53 , 56 ].…”

“…A recent review by Reis et al [ 56 ] also confirms that deep endometriosis appears to be more resistant to regression upon medical treatment. According to the literature, some authors found a substantial volume reduction during OCP and norethisterone acetate (NETA) therapy [ 57 ], but this was not confirmed by other more recent studies [ 53 , 56 ]. Indeed, PRs may be present, but biologically inactive.…”

“…Safety nevertheless remains a concern, as patients may need long-term periods of therapy during their advanced reproductive years, and the risk of venous or arterial thrombosis is not negligible [ 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 ]. The relative risk (RR) is dependent on the type of progestins used for estroprogestin preparation, but progestin-only preparations (NETA and desogestrel pills) were not shown to increase the risk of venous thromboembolism [ 67 ].…”

“…In a recent review, Reis et al [ 56 ] summarized the effect of progestins on endometriotic lesions as generating different levels of downregulation of ERs, a drop in local E2 production, a reduction in inflammation, and creation of a pseudo-pregnancy condition. However, the impact of progestogens on the morphology and vascularization of ectopic endometrial tissue and atrophy is much more questionable [ 77 , 78 , 79 , 80 , 81 ].…”