{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T17:59:45Z","timestamp":1789840785686,"version":"4.0.1"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T00:00:00Z","timestamp":1761523200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Background and objective<\/jats:title>\n                    <jats:p>\n                      Ovarian endometriosis (OE), characterized by endometriotic cysts, adversely affects ovarian function and comprises\n                      <jats:italic>in vitro<\/jats:italic>\n                      fertilization and embryo transfer (IVF-ET) outcomes. Acupoint application therapy (AAT), which integrates transdermal drug delivery with acupoint stimulation, may offer therapeutic benefits; however, its underlying mechanisms remain unclear.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this randomized trial, 81 IVF-ET patients were stratified into: a treatment group comprising OE patients (n=27) undergoing a gonadotropin hormone-releasing hormone (GnRH) antagonist protocol with medicated AAT, a placebo group consisting of OE patients (n=26) following an identical protocol but receiving a sham patch, and a control group, including patients with male-factor infertility (n=28) undergoing the standard protocol without additional interventions. Follicular fluid metabolomics (assessed by Ultra High-Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS\/MS) System)and IVF parameters were analyzed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Significant intergroup differences were observed (one-way ANOVA,\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt; 0.05). The treatment group exhibited a shorter Gn duration (9.00 \u00b1 0.68 days) compared to the placebo group (10.62 \u00b1 2.43 days;\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt; 0.05), with a duration comparable to the male-factor control group (9.32 \u00b1 1.89 days; NS). Similarly, the total Gn dose was lower in the treatment group (2112.50 \u00b1 483.17 IU) than in the placebo group (2549.04 \u00b1 677.44 IU;\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt; 0.05), and comparable to the control group (2105.89 \u00b1 690.24 IU; NS). Regarding IVF outcomes, the treatment group yielded more oocytes retrieved (12.41 \u00b1 7.27) than the placebo group (8.85 \u00b1 7.89;\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt; 0.05), though fewer than the control group (15.25 \u00b1 7.77). Fertilized oocytes were also higher in the treatment group (7.59 \u00b1 4.58) compared to the placebo group (4.46 \u00b1 3.40;\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt; 0.05), but fewer than in the control group (9.21 \u00b1 4.82). The number of transferable embryos was comparable between the treatment group (3.33 \u00b1 2.30) and the control group (3.43 \u00b1 2.13; NS), and significantly higher than in the placebo group (1.69 \u00b1 1.87;\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt; 0.05). Furthermore, the treatment group produced more high-quality embryos (3.04 \u00b1 1.89) than the placebo group (1.35 \u00b1 1.99;\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt; 0.05), and more than the control group (2.43 \u00b1 1.95). No significant intergroup difference was found in fertilization rates (64.40% vs. 62.90% vs. 60.90%; NS). However, the high-quality embryo rate was significantly higher in the treatment group (47.02%) compared to both the placebo (31.15%;\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt; 0.05) and control (29.05%;\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt; 0.05) groups. Finally, the treatment group demonstrated a significantly greater reduction in peri-menstrual abdominal pain scores (\u0394=\u22121.15 \u00b1 0.36) compared to the placebo group (\u0394=\u22120.35 \u00b1 0.49; F = 6.84,\n                      <jats:italic>P<\/jats:italic>\n                      = 0.01). Metabolomic analysis revealed that the steroid hormone biosynthesis pathway was the most significantly disturbed in OE patients, characterized by markedly elevated levels of key intermediates such as 17\u03b1-hydroxyprogesterne. Critically, the levels of 17\u03b1-hydroxyprogesterone exhibited a significant negative correlation with oocyte yield (r = -0.286, p = 0.012), directly linking this metabolic dysregulation to impaired clinical outcome. Furthermore, oxidative stress metabolites showed a strong positive correlation with the luteinization marker 20\u03b1-hydroxy-4-pregnen-3-one (r = 0.43, p = 0.001), suggesting a potential interaction between oxidative stress and aberrant steroidogenesis. The AAT intervention effectively normalized this dysregulated steroidogenic profile, which underpinned the observed therapeutic benefits.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>AAT significantly alleviates peri-menstrual pain and enhances IVF outcomes in ovarian endometriosis patients, which may be attributed to the restoration of granulosa cell steroid metabolism, evidenced by normalized levels of 17\u03b1-hydroxyprogesterone and attenuation of oxidative stress.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical trial registration<\/jats:title>\n                    <jats:p>\n                      <jats:uri>https:\/\/www.chictr.org.cn\/<\/jats:uri>\n                      , identifier ChiCTR2200057339.\n                    <\/jats:p>\n                  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