In the present study, we utilized the ASL-MRI technique to evaluate perfusion of myometrium, and showed the ability to perform the technique by the findings that (1) normal myometrium perfusion during the secretory phase was significantly lower than that of the proliferative phase, (2) perfusion of myometrium on the fibroid-positive side was significantly higher than that of the fibroid-negative side and (3) with GnRHa treatment, ASL perfusion in myometrium decreased to 39% on average.
The two most common methods for measuring perfusion with MRI are based on dynamic susceptibility contrast (DSC) and arterial spin labeling (ASL) (Wolf and Detre 2007). As MR perfusion using ASL does not need contrast medium, and ASL signals disappear in few seconds, it is a non-invasive examination and can be performed repeatedly even in renal failure patients (Telischak et al. 2015). ASL MRI is useful to diagnose various cerebrovascular diseases which cause a disorder of perfusion (Detre et al. 2012), and it has also been used to examine normal brain function (Wang et al. 2003; Telischak et al. 2015). We applied ASL-MRI to the female pelvis in order to evaluate perfusion in the myometrium. In our study, ASL perfusion in normal myometrium during the secretory phase was lower than in the proliferative phase. In accordance with our findings, ultrasound techniques designed to measure blood flow also revealed that myometrium showed lower tissue blood flow during the secretory phase compared to the proliferative phase by laser Doppler fluxmetry and power Doppler angiography (Gannon et al. 1997; Raine-Fenning et al. 2004a). During the proliferative phase, small vessels, including the spiral and straight arterioles in the inner myometrium develop (Blackwell and Fraser 1988). Additionally, the increase of serum estradiol levels and the decrease in microvascular resistance during the proliferative phase are known to increase blood flow (de Vries et al. 1990).
Secondly, we used the ASL-MRI technique to demonstrate the influence of fibroids in myometrium perfusion. Doppler ultrasound examination revealed that in women with fibroids, blood flow in the uterine artery was higher than in women without fibroids (Sladkevicius et al. 1996; Kurjak et al. 1992; Alataş et al. 1997). However, it is difficult to evaluate perfusion of local myometrium. Using the ASL technique, we were able to evaluate perfusion in local regions by setting the region of interest (ROI). In our study, we evaluated the perfusion of myometrium beneath the endometrium, and found that all three types, submucosal, intramural, and subserosal fibroids, increased blood perfusion in the adjacent myometrium. Importantly, the ASL signal in the myometrium on the fibroid-positive side was higher than that of fibroid-negative side, implying that fibroids may cause an imbalance of blood distribution in the myometrium.
In recent studies, fibroids have been shown to exhibit high levels of pro-angiogenic factors, which cause an increase in angiogenesis and vascular density in the normal myometrium surrounding fibroids (Tal and Segars 2014). Vascular abnormalities due to the presence of fibroids might be associated with clinical symptoms such as abnormal bleeding, implantation failure and gestation discontinuation (Deligdish and Loewenthal 1970; Buttram and Reiter 1981). In another report, endometrial and sub-endometrial perfusion was impaired in women with unexplained subfertility (Raine-Fenning et al. 2004b). These data imply that an adequate blood supply to the endometrium is required for implantation. In some patients with fibroids, one of the symptoms is infertility. Meta-analyses showed that submucosal but not subserosal fibroids have a negative effect on pregnancy rate, while conclusions regarding intramural lesions have been conflicting (Somigliana et al. 2007; Pritts et al. 2009). Therefore, subserosal and intramural fibroids are not routinely removed for infertility treatment. However, in some patients, removal of fibroids could improve pregnancy rate and decrease miscarriage (Brady et al. 2013). Gynecologists need to accurately assess the effectiveness of surgical intervention of uterine fibroids. In our study, although it included a small numbers of patients, all three types of fibroids caused an imbalance of perfusion in uterine myometrium. Moreover, there was no correlation between ASL perfusion indexes and types or the size of fibroid. Further study is needed to investigate the relationship between uterine perfusion and reproductive outcomes.
Finally, we confirmed that the ASL-MRI technique could detect the decrease of myometrial blood supply with GnRHa treatment. The use of GnRHa prior to fibroid surgery reduces fibroid volume, and also improves pre-operative anemia, and intra-operative blood loss (Lethaby et al. 2001). GnRHa treatment led to a decrease in micorovascular density in tissue of uterine fibroids (Khan et al. 2010), and a decrease in angiogenesis-related factors such as VEGF, bFGF, and PDGF (Di Lieto et al. 2005). Consistent with our ASL-MRI finding, there are some reports that GnRHa treatment reduced the uterine blood flow evaluated with Doppler ultrasound (Matta et al. 1988; Aleem and Predanic 1995). However, in the present study, there is no correlative relationship between the decreasing ratio of fibroid size and change in ASL index before and after GnRHa, suggesting that other factors might be involved in decreasing fibroid size.
In the present study, we could not compare ASL signal data with perfusion data obtained by using contrast agents, due to the clinical limitations in which contrast agents were not used for patients with fibroids in our clinic. In the brain MRI, it appears that blood flow can be estimated correctly in the grey matter of the brain by using ASL techniques (Wintermark et al. 2005). Further study is needed to determine whether ASL signal actually correlates to the blood flow in the uterus.