Uterine fibroids: a critical appraisal of novel treatments

Uterine fibroids (leiomyomas) are highly prevalent and can substantially impair women’s quality of life, most commonly through abnormal uterine bleeding (AUB). Current treatment options range from medical therapy to minimally invasive procedures and surgery. This thesis investigates novel treatment perspectives by exploring the role of angiogenesis in fibroid-related symptoms, optimising patient selection for uterine artery embolisation (UAE), and critically evaluating the development and implementation of ulipristal acetate as a medical therapy. Together, the studies emphasise the importance of personalised, evidence-based care and responsible introduction of new treatments. Part I focuses on the pathophysiology of fibroid-related symptomatology, focussing on angiogenesis. The endometrium undergoes cyclical regeneration, requiring tightly regulated vascular remodelling. Disruption of angiogenic balance may lead to AUB and impaired fertility. Two systematic reviews were conducted. Chapter 2 examined endometrial angiogenesis in women with AUB without fibroids. Thirty-five studies showed increased pro-angiogenic factors and immature vessel characteristics in endometrial AUB (AUB-E), supporting the hypothesis that unstable and leaky vasculature contributes to AUB. In iatrogenic AUB (AUB-I), progestogen-based therapies were associated with altered angiogenesis, which appeared to normalise over time. Key pathways involved included HIF, VEGF, FGF, and Ang-Tie. Chapter 3 reviewed angiogenesis in women with fibroids, including those with fibroid-induced AUB (AUB-L), infertility, or receiving medical treatment. Fifteen studies demonstrated increased expression of pro-angiogenic factors such as VEGF, ADM, and eNOS, particularly in women with AUB-L. Despite this, microvessel density was unchanged, suggesting alternative angiogenic mechanisms such as vessel enlargement and coalescence. The presence of venous lakes indicated vascular immaturity. In infertile women with fibroids, reduced angiogenic activity may impair implantation. These findings highlight angiogenesis as a potential therapeutic target and underscore its heterogeneous role in fibroid-related symptoms. Part II addresses optimisation of patient selection and counselling for UAE. An individual participant data meta-analysis (IPD-MA) of RCTs comparing UAE with surgery was performed. Seven trials were included, providing data from 766 women. At 12 months, health-related quality of life (HRQoL) was significantly lower after UAE. Reintervention rates were 8% at 12 months and 16% at 24 months, with increasing age associated with a lower reintervention risk. Treatment effects differed by patient characteristics: women with larger fibroids benefited more from surgery, whereas women with higher BMI had better outcomes after UAE. These results support personalised treatment selection based on individual patient-characteristics. Part III evaluates ulipristal acetate as a medical (pre-)treatment for fibroids, focusing on its rapid adoption and subsequent decline. Ulipristal was implemented quickly, despite limited comparative evidence. Rare cases of severe drug-induced liver injury (DILI) led to regulatory restrictions and eventual withdrawal. In Chapter 6, concerns are raised regarding the generalisability of the registrational trials and the lack of cost-effectiveness and comparative outcome data. Chapter 7 presents the MYOMEX-1 trial, a double-blind non-inferiority RCT comparing ulipristal with GnRH agonists as pretreatment before laparoscopic myomectomy. Long-term outcomes, including bleeding, QoL, and haemoglobin levels, were comparable between groups. Although underpowered, the study suggested similar effectiveness, with no significant liver safety signals observed. Chapters 8 and 9 critically analyse the risk–benefit balance and regulatory pathway of ulipristal. Although the absolute risk of severe DILI was very low, regulatory decisions varied, highlighting challenges in balancing rare risks against surgical morbidity. The ulipristal case illustrates broader issues in trial design, regulatory evaluation, post-marketing surveillance, and clinical guideline development. Finally, recommendations are made regarding improved understanding of pathophysiology through biobanking, cautious implementation of new therapies using core outcome sets, and stimulation of personalised medicine through approaches such as IPD-MA. This thesis advances insight into fibroid-related angiogenesis, informs clinical decision-making between UAE and surgery, and highlights the need for careful, collaborative, and evidence-based introduction of innovative treatments.