{"paper_id":"913e4939-f384-4fec-8b40-c4b4da5069a9","body_text":"ABSTRACT\nIntroduction\nMedical therapy is crucial in the long-term management of endometriosis, and its clinical efficacy must be balanced with a favorable safety profile.\nAreas covered\nThis review aims to provide a comprehensive overview of available drugs for the treatment of endometriosis, with an emphasis on their safety. A literature search was conducted using MEDLINE. EMBASE. and the Cochrane Library. Reference lists of relevant articles and recent book chapters were also examined.\nExpert opinion\nFirst-line therapies include combined contraceptives and progestins, both effective in reducing pain. Combined contraceptives commonly cause breakthrough bleeding, nausea, headaches, breast tenderness, and libido changes. Progestins may lead to depression, decreased libido, weight gain, breast tenderness, and lipid alterations. Gonadotropin-releasing hormone agonists are second-line options but are limited by hypoestrogenic side effects, including vasomotor symptoms, urogenital atrophy, and bone mineral density (BMD) loss. Add-back therapy with norethindrone acetate or low-dose combined contraceptives mitigates these effects. GnRH antagonists provide immediate suppression without flare-up and may improve adherence; however, hot flushes and BMD loss remain concerns. While all hormonal therapies are suppressive rather than curative, optimizing safety and tolerability is essential for sustained use and symptom control.\nArticle highlights\nMedical therapy plays a crucial role in managing endometriosis-related pain; long-term treatment strategies should effectively balance clinical efficacy (control of pain symptoms and prevention of recurrence) with an acceptable safety profile.\nProgestins are a first-line treatment of endometriosis-related pain; they are well tolerated over the long term. Their main adverse effects are breakthrough bleeding, depression, decreased libido, breast tenderness, lipid alterations, weight gain and fluid retention.\nCombined contraceptives are a first-line treatment of endometriosis-related pain; their most common adverse effects are breakthrough bleeding, nausea, headaches, abdominal cramping, breast tenderness, and changes in vaginal discharge or libido. Most side effects of combined contraceptives are mild and often resolve with continued use or switching to a different formulation. The standard combined contraceptive regimen may slightly increase the risk of adverse events compared to the continuous regimen.\nGonadotropin-releasing hormone agonists may cause several adverse effects such as alteration of lipid profile, depression, flushes, urogenital atrophying and loss of bone mineral density (BMD) that limit their long-term use. The intensity of these adverse effects can be decreased with the administration of an appropriate add-back therapy with norethindrone acetate or a low-dose combined contraceptive.\nGonadotropin-releasing hormone antagonists may enhance long-term patient adherence to treatment because they effectively improve pain with minimal adverse effects, mainly hot flushing and loss of BMD.\nDisclosure form\nThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.\nAuthors contribution\nSimone Ferrero: Writing of the first draft, supervision\nFabio Barra: Revision of the draft\nGiulia Vatteroni: Literature analysis\nFrancesco Paolo Rosato: Data analysis\nGiulio Evangelisti: Literature analysis\nMichele Paudice: Data analysis\nValerio Gaetano Vellone: Data analysis\nData availability statement\nThe authors confirm that the data supporting the findings of this study are available within the article.","source_license":"CC0","license_restricted":false}