{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T13:40:42Z","timestamp":1793108442233,"version":"4.5.0"},"reference-count":208,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2020,5,15]],"date-time":"2020-05-15T00:00:00Z","timestamp":1589500800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["201876\/2017-5"],"award-info":[{"award-number":["201876\/2017-5"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,6,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>BACKGROUND<\/jats:title>\n                    <jats:p>Despite intense research, it remains intriguing why hormonal therapies in general and progestins in particular sometimes fail in endometriosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>OBJECTIVE AND RATIONALE<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>SEARCH METHODS<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>OUTCOMES<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>WIDER IMPLICATIONS<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/humupd\/dmaa009","type":"journal-article","created":{"date-parts":[[2020,2,25]],"date-time":"2020-02-25T15:13:34Z","timestamp":1582643614000},"page":"565-585","source":"Crossref","is-referenced-by-count":152,"title":["Progesterone receptor ligands for the treatment of endometriosis: the mechanisms behind therapeutic success and failure"],"prefix":"10.1093","volume":"26","author":[{"given":"Fernando M","family":"Reis","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil"},{"name":"Department of Gynecology Obstetrics II and Reproductive Medicine, Facult\u00e9 de M\u00e9decine, Assistance Publique \u2013 H\u00f4pitaux de Paris (AP-HP), H\u00f4pital Universitaire Paris Centre (HUPC), Centre Hospitalier Universitaire (CHU) Cochin, Paris, France"},{"name":"Institut Cochin, INSERM U1016, Universit\u00e9 Paris Descartes, Sorbonne Paris Cit\u00e9, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larissa M","family":"Coutinho","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil"},{"name":"Division of Obstetrics and Gynecology, Department of Biomedical, Experimental and Clinical Sciences, Careggi University Hospital University of Florence, Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Vannuccini","sequence":"additional","affiliation":[{"name":"Division of Obstetrics and Gynecology, Department of Biomedical, Experimental and Clinical Sciences, Careggi University Hospital University of Florence, Florence, Italy"},{"name":"Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy"},{"name":"Department of Gynecology Obstetrics II and Reproductive Medicine, Facult\u00e9 de M\u00e9decine, Assistance Publique \u2013 H\u00f4pitaux de Paris (AP-HP), H\u00f4pital Universitaire Paris Centre (HUPC), Centre Hospitalier Universitaire (CHU) Cochin, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9ric","family":"Batteux","sequence":"additional","affiliation":[{"name":"Institut Cochin, INSERM U1016, Universit\u00e9 Paris Descartes, Sorbonne Paris Cit\u00e9, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Chapron","sequence":"additional","affiliation":[{"name":"Department of Gynecology Obstetrics II and Reproductive Medicine, Facult\u00e9 de M\u00e9decine, Assistance Publique \u2013 H\u00f4pitaux de Paris (AP-HP), H\u00f4pital Universitaire Paris Centre (HUPC), Centre Hospitalier Universitaire (CHU) Cochin, Paris, France"},{"name":"Institut Cochin, INSERM U1016, Universit\u00e9 Paris Descartes, Sorbonne Paris Cit\u00e9, Paris, 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