RESUMO
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.
Assuntos
Endometriose/tratamento farmacológico , Ligantes , Doenças Peritoneais/tratamento farmacológico , Receptores de Progesterona/agonistas , Endometriose/epidemiologia , Endometriose/metabolismo , Endométrio/anormalidades , Feminino , Fármacos para a Fertilidade Feminina/uso terapêutico , Humanos , Doenças Peritoneais/epidemiologia , Doenças Peritoneais/metabolismo , Progesterona/uso terapêutico , Progestinas/uso terapêutico , Receptores de Progesterona/metabolismo , Resultado do Tratamento , Doenças Uterinas/tratamento farmacológicoRESUMO
STUDY OBJECTIVE: To evaluate the long-term impact of laparoscopic excision of endometriosis on quality of life through pain reduction as measured by the Endometriosis Health Profile-30 (EHP-30) in uterine-sparing (preservation of the uterus and at least 1 ovary) and nonuterine-sparing (removal of the uterus) surgery. DESIGN: Cohort study. SETTING: Academic medical center. PATIENTS: Sixty-one women who had undergone laparoscopic excision of endometriosis for pelvic pain were enrolled in a tissue-procurement study. INTERVENTIONS: Patients who had previously completed an EHP-30 preoperatively and at 4 weeks postoperatively were mailed a copy of the EHP-30 2.6 to 6.8 years after their index surgery. MEASUREMENTS AND MAIN RESULTS: The primary outcome was quality of life as measured by changes in the EHP-30 scores before their index surgery and those measured weeks and years later. The secondary outcome was a comparison of the EHP-30 scores between patients who underwent excision of endometriosis alone and those who underwent excision of endometriosis with hysterectomy +/- oophorectomy. From 2011 to 2015, 61 women underwent laparoscopic excision of endometriosis for pelvic pain. Forty-six of the 61 patients completed the EHP-30 for a response rate of 75%. The patients demonstrated significant improvement in all 5 scales of the EHP-30 (pain, control and powerlessness, emotional well-being, social support, and self-image) at 4 weeks postoperatively (p <.001), which persisted for up to 6.8 years in follow-up (p <.001) when compared with their baseline scores. The improvement in EHP-30 scores did not differ by American Society for Reproductive Medicine staging or index surgery. Definitive surgery (total laparoscopic hysterectomy/bilateral salpingo-oophorectomy) was not associated with improved outcomes when compared with uterine-sparing surgery. CONCLUSION: Laparoscopic excision of endometriosis offers improvement in all quality-of-life domains as measured by the EHP-30, including a reduction in pain, an effect that may persist for up to 6.8 years. These findings suggest that laparoscopic excision of endometriosis with uterine preservation can be considered as an option for discussion during counseling for treatment of endometriosis.