Safety of current strategies to manage moderate to severe pain in patients with endometriosis

Simone Ferrero, Ferrero S, Barra F, Fabio Barra, Vatteroni G, Giulia Vatteroni, Rosato FP, Francesco Paolo Rosato, Francesco Rosato, Giulio Evangelisti, Evangelisti G, Paudice M, Michele Paudice, Valerio Gaetano Vellone, Vellone VG
Expert opinion on drug safety · 2025 · vol. 25(2) , pp. 245–258 · doi:10.1080/14740338.2025.2547017 · PMID:40788342 · W4413101888
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⚙ AI-generated summary by gemini-2.5-flash-lite, 2026-06-07 ⓘ

This review evaluates the safety of hormonal therapies for endometriosis pain, finding combined contraceptives and progestins effective but noting side effects, while GnRH agonists and antagonists offer alternatives with distinct safety concerns like hypoestrogenism and bone density loss.

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⚙ AI-generated deep summary by claude@2026-07, 2026-07-16 · read from full text ⓘ

This paper is a narrative review that uses MEDLINE, EMBASE, and the Cochrane Library (plus reference lists and book chapters) to summarize drug strategies for moderate to severe endometriosis-related pain, focusing on safety alongside efficacy. It reports that combined contraceptives and progestins are first-line options with common adverse effects including breakthrough bleeding and related symptoms for combined contraceptives, and depression, libido changes, weight gain, and lipid alterations for progestins. Second-line options include GnRH agonists, limited by hypoestrogenic effects such as vasomotor symptoms and bone mineral density loss, and GnRH antagonists, which suppress pain without flare but still raise concerns about hot flushes and BMD loss. The review is not a primary clinical trial and provides an expert-opinion synthesis rather than a direct comparative effectiveness analysis. This paper is centrally about endometriosis — it reviews current medical therapies for endometriosis-related pain with an emphasis on their safety profiles.

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Abstract

INTRODUCTION: Medical therapy is crucial in the long-term management of endometriosis, and its clinical efficacy must be balanced with a favorable safety profile. AREAS COVERED: This 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. EXPERT OPINION: First-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.
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ABSTRACT Introduction Medical therapy is crucial in the long-term management of endometriosis, and its clinical efficacy must be balanced with a favorable safety profile. Areas covered This 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. Expert opinion First-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. Article highlights Medical 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. Progestins 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. Combined 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. Gonadotropin-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. Gonadotropin-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. Disclosure form The 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. Authors contribution Simone Ferrero: Writing of the first draft, supervision Fabio Barra: Revision of the draft Giulia Vatteroni: Literature analysis Francesco Paolo Rosato: Data analysis Giulio Evangelisti: Literature analysis Michele Paudice: Data analysis Valerio Gaetano Vellone: Data analysis Data availability statement The authors confirm that the data supporting the findings of this study are available within the article.

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Condition tags

endometriosis

MeSH descriptors

Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis

Citation neighborhood

Papers in the corpus that this work cites (lower rings, blue) and that cite this one (upper rings, green). Dot size scales with the paper's in-corpus citation count — bigger dot = more influential within the endo/adeno field. Click a dot to open that paper. [ expand to 2 hops ] — adds papers reached through this work's immediate citers/citees. Heavier; up to 60 extra dots.

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