The Levonorgestrel Intrauterine System Attenuates the Expression of Angiopoietin-1, Angiopoietin-2, and Vascular Endothelial Growth Factor in Adenomyosis

<b>Background/Objectives</b>: Adenomyosis is characterized by aberrant endometrial invasion and heavy menstrual bleeding, with angiogenesis being implicated as a key mechanism of this condition. We compared vascular endothelial growth factor (VEGF), angiopoietin-1 (ANGPT-1), and angiopoietin-2 (ANGPT-2) expression in eutopic and ectopic endometria from patients with adenomyosis and evaluated whether the levonorgestrel intrauterine system (LNG-IUS) modulates these angiogenic markers. <b>Methods</b>: In a case-control analysis, specimens from patients with adenomyosis without an LNG-IUS (<i>n</i> = 20), those with adenomyosis with prior LNG-IUS insertion (<i>n</i> = 18), and controls (<i>n</i> = 12) were analyzed. Immunohistochemistry with H-scores was used to assess protein expression in eutopic and ectopic tissues. <i>ANGPT1</i>, <i>ANGPT2</i>, and <i>VEGFA</i> mRNA in eutopic endometrial tissue were quantified by qRT-PCR. <b>Results</b>: In untreated adenomyosis patients, ectopic endometria showed higher protein expression than eutopic tissue for ANGPT-1, ANGPT-2, and VEGF (all <i>p</i> ≤ 0.05). The LNG-IUS was associated with significantly lower expression of all three markers in both eutopic and ectopic tissue (all <i>p</i> < 0.01), with eutopic levels approaching those of controls. qRT-PCR findings corroborated the decrease in <i>ANGPT1</i>, <i>ANGPT2</i>, and <i>VEGFA</i> transcript levels after LNG-IUS insertion (all <i>p</i> < 0.05). <b>Conclusions</b>: Adenomyosis is characterized by upregulated angiogenic signaling in both eutopic and ectopic endometria. The LNG-IUS attenuates ANGPT-1, ANGPT-2, and VEGF expression at both the protein and transcript levels, suggesting that modulation of angiogenic pathways may contribute to its therapeutic benefit in abnormal uterine bleeding associated with adenomyosis.