Advancements in diagnosis and treatment of Adenomyosis

In this thesis, we aimed to study how we can improve the diagnosing of adenomyosis by imaging the uterus in part I, especially using ultrasound and considering the assessment of the uterine junctional zone. In part II, we aimed to investigate the role of angiogenesis in the pathogenesis and clinical manifestation of adenomyosis and to explore whether this mechanism could be a potential treatment target. In chapter 2 (part I), we explored whether the terminology used to describe ultrasound images of adenomyosis needed to be better defined in a modified Delphi study. There was consensus on the need to distinguish between direct and indirect features of adenomyosis. Direct features indicate the presence of ectopic endometrium in the myometrium, while indirect features reflecting changes in the myometrium secondary to presence of endometrial tissue in the myometrium. In chapter 3 (Part I), a comprehensive literature review was conducted to investigate the accordance on the definition of the junctional zone across different diagnostic approaches and examine how the imaging findings can be linked to histological findings. The conclusion in this review was that on histology, gradual tissue changes distinguish the junctional zone from the middle and outer myometrium. The thickness of the junctional zone was reported larger on MRI than on TVUS images. Clinicians should be aware that findings on MRI cannot readily be extrapolated to ultrasound. The focus of the second part of this thesis was on the role of angiogenesis in adenomyosis. We hypothesized that the level of angiogenesis is increased in the ectopic and eutopic endometrium of patients with adenomyosis in comparison with patients without adenomyosis. In chapter 4 we performed a systematic search and found an increased mean vascular density (MVD) and angiogenic properties in the ectopic and eutopic endometrium compared to control endometrium. Although the association has not sufficiently been studied yet, it is likely that increased angiogenesis leads to fragile and more permeable vessels resulting in adenomyosis-related AUB and possibly subfertility. Since VEGF stimulates both angiogenesis and lymph-angiogenesis, the presence of lymph vessel angiogenesis was investigated in a retrospective matched case-control study described in chapter 5. The blood and lymph vessel densities were higher in the ectopic and eutopic endometrium than in control endometrium in patients that were in the proliferative phase of the menstrual cycle. The results of this study are evidence for the presence of increased angiogenesis and lymph angiogenesis in the (ectopic) endometrium of adenomyosis patients versus controls. In chapter 6, we investigated the angiogenic potential of endometrial and myometrial biopsies collected in a prospective study from patients with and without adenomyosis. The results confirm that adenomyosis tissue, in particular endometrium overlying adenomyosis lesions, has angiogenic potential and provides evidence for our hypothesis that angiogenesis plays a role in the pathogenesis of adenomyosis. Since the results of the studies described in the chapter above suggest a pivotal role for angiogenesis in the pathophysiology of adenomyosis, we investigated the effect of anti-angiogenic therapy in adenomyosis in an in vivo mouse model and described the results in chapter 7. This study showed that angiogenesis inhibition through oral axitinib treatment reduces the severity of adenomyosis. The hypothesis why this potential therapy is promising and might aid to reverse uterine aging is described in chapter 8. In our regard, anti-angiogenic therapy may provide therapeutic options. Finally, chapter 9 discusses the answers to the research questions of this thesis and provides clinical implications and suggestions for future research.