Anti-Angiogenic Therapy as a Potential Treatment for Adenomyosis

Academic Background

Adenomyosis is a common gynecological condition characterized by endometrial tissue invading the myometrium, resulting in abnormal uterine bleeding, dysmenorrhea, and infertility. Despite its significant impact on women’s quality of life and public health, the etiology of the disease remains unclear. Currently, treatment options for adenomyosis primarily rely on hormonal therapies; however, many patients experience severe side effects or incomplete symptom relief, leading them to resort to more radical solutions such as uterine artery embolization or hysterectomy. These methods, however, are unsuitable for women wishing to preserve their fertility.

In recent years, studies have shown significantly increased markers of angiogenesis in the endometrial tissues of adenomyosis patients, suggesting that angiogenesis may play a crucial role in the pathogenesis and development of this disease. Angiogenesis, the process by which new capillaries sprout from existing blood vessels, is fundamental not only to physiological processes but also to various pathological conditions. Based on this finding, researchers propose that anti-angiogenic therapy could be a potential treatment option for adenomyosis.

Paper Information

This study was authored by Marissa J. Harmsen, Lynda J. M. Juffermans, Muara O. Kroon, Arjan W. Griffioen, and Judith A. F. Huirne, who are affiliated with the Department of Obstetrics and Gynecology, Angiogenesis Laboratory for Medical Oncology, and Cancer Center Amsterdam, all part of Amsterdam UMC in the Netherlands. The paper was published in 2025 in the journal Angiogenesis under the title Anti-angiogenic therapy as potential treatment for adenomyosis.

Research Methods

1. Model Development and Validation

The study began by establishing a mouse model of adenomyosis using CD-1 mice. Neonatal mice were administered tamoxifen (1 mg/kg) from days 2 to 5 post-birth to induce adenomyosis. Six weeks later, the mice were randomly divided into three groups: one group received a low dose of axitinib (3 mg/kg, n=34), another received a high dose of axitinib (25 mg/kg, n=34), and the third served as a placebo group (n=34). Histological methods were employed to assess the prevalence and severity of adenomyosis, and the adenomyosis severity index (ASI) was calculated.

2. Histological and Immunohistochemical Analysis

The uterine tissues of the mice were split into two parts: one for paraffin embedding followed by hematoxylin and eosin (H&E) staining and immunohistochemistry (IHC) analysis, and the other for RNA extraction and real-time quantitative PCR (RT-qPCR). Immunohistochemical staining was performed to detect the expression of α-smooth muscle actin (α-SMA), CD31, and vimentin in order to evaluate uterine structural changes and microvascular density (MVD).

3. Gene Expression Analysis

RT-qPCR was used to measure the expression levels of angiogenesis-related genes, including VEGF-A, VEGF-R1, VEGF-R2, PLGF, and BFGF, to determine the impact of axitinib on angiogenesis.

Key Findings

1. Successful Induction of Adenomyosis in a Mouse Model

All mice treated with tamoxifen successfully developed adenomyosis, whereas no adenomyosis was observed in the placebo-treated mice. Histological analysis revealed ectopic infiltration of endometrial glands into the myometrium and significant disruption of the myometrial architecture in the tamoxifen-treated groups.

2. Axitinib Effectively Reduced the Severity of Adenomyosis

• Prevalence: The prevalence of adenomyosis did not differ significantly among the groups (low-dose group: 90.0%, high-dose group: 85.3%, placebo group: 88.2%).
• Severity: The high-dose axitinib group exhibited a significantly lower prevalence of high-grade (grade ²⁄₃) adenomyosis compared to the placebo group (55.9% vs. 79.4%). The adenomyosis severity index was reduced by 48% in the low-dose axitinib group compared to the placebo group.
• Gene Expression: Axitinib treatment significantly downregulated the expression of angiogenesis-related genes such as VEGF-R1, VEGF-R2, and CD31.

3. Changes in Uterine Wall Parameters and Microvascular Density

Mice treated with axitinib showed reduced uterine myometrial thickness and lower microvascular density compared to the placebo group, indicating that anti-angiogenic therapy effectively mitigated the progression of adenomyosis.

Conclusions and Implications

The study demonstrates that the anti-angiogenic drug axitinib significantly reduces the severity of adenomyosis, decreasing ectopic endometrial infiltration and disrupting myometrial structure. These findings provide new insights into the potential of anti-angiogenic therapies, particularly for women who wish to retain their fertility. Additionally, the study suggests that low doses of anti-angiogenic drugs may be sufficient to achieve therapeutic effects, potentially reducing the risk of side effects.

Research Highlights

1. Innovative Treatment Approach: This is the first study to apply anti-angiogenic therapy in an adenomyosis animal model, verifying its therapeutic potential.
2. Low-Dose Effectiveness: The research highlights that low doses of axitinib can significantly alleviate symptoms, providing key guidance for clinical dosing strategies.
3. Comprehensive Evaluation: The study comprehensively assessed treatment efficacy through histology, immunohistochemistry, and gene expression analysis.

Future Directions

While the results are promising, further investigations are needed to explore the safety, optimal timing, and localized delivery of anti-angiogenic drugs. Additionally, research should focus on identifying common mechanisms of action and potential side effects of different anti-angiogenic agents.

This research opens a new avenue for the treatment of adenomyosis, offering significant scientific and clinical potential.