Chronic pelvic pain (CPP) is one of the most severe symptoms of the pelvic venous disorder (PeVD) caused by valvular incompetence of ovarian veins and pelvic venous plexuses (1). Chronic positional pain varies in terms of intensity and duration and is frequently accompanied by dyspareunia and urgent bladder irritability, which can extend to the posteromedial thigh or buttock and has an extremely negative impact on quality of life (QOL) (2, 3). Despite increasing awareness of this condition, the precise etiology of CPP secondary to PeVD remains uncertain and is probably related to multiple factors. Pelvic vein incompetence with the retrograde flow in the varicose utero-ovarian plexus has been implicated as one of the most important causes of CPP secondary to PeVD (4).

Ovarian vein embolization (OVE) has been recommended in cases with a 2B level of evidence for the treatment of PeVD, has a low rate of morbidity or complications, and has largely replaced open surgical intervention (5, 6). The goal of OVE is to occlude incompetent varicose veins to reduce excessive blood flow within the pelvic vein plexus. As previously reported (7, 8), conventional embolic materials used for OVE include sclerosing agents and metal coils and have a clinical efficacy ranging from 58 to 93%. However, sclerotherapy involves a difficult monitoring process using fluoroscopy, and coils pose risks of migration, hypersensitivity, or further recanalization (7–13). Although, a consensus on which embolic materials are most suitable for OVE is lacking.

Liquid embolic materials, such as N-butyl-2 cyanoacrylate (NBCA), are efficiently used to achieve hemostasis to treat acute arterial hemorrhage in various organs (14). In particular, the considerable advantage of a high rate of polymerization makes NBCA a potential alternative in PeVD. Nevertheless, to the best of our knowledge, there are few reports in the literature on the embolization of PeVD with Glubran-2 for the treatment of CPP, and consensus on the efficacy and safety of this treatment has not been reached. The purpose of the present study was to investigate the safety and efficacy of OVE with NBCA Glubran-2 for the treatment of PeVD.

Glubran-2 was employed as the sole embolic material in 18 cases. In 4 cases, Glubran-2 embolization was augmented using microcoils at the opening of the varicose ovarian vein trunk to reduce the risk of non-target embolization from overflow during the procedure (Figure 2), and the mean number of microcoils used was 4 ± 1. Glubran-2 was used for rescue embolization in 3 cases due to CPP recurrence 1 month after initial embolization using microcoils (Figure 3). The concentration ratio of Glubran-2 to ethiodized oil was 1:3–1:4, and the mean injected volume was 3.7 ± 1.0 ml (range, 3–5 ml). Final venography revealed complete occlusion of all targeted varicose veins; thus, embolization with Glubran-2 was technically successful for all patients. No Glubran-2-related complications occurred mid-procedure or post-intervention.

Pre-intervention, 3 patients experienced mild pain, 6 patients experienced moderate pain, and 12 patients experienced severe pain. During follow-up (mean 62 ± 38 months; range, 12–102 months), neither persistent nor recurrent CPP requiring repeat endovascular treatment or surgery was observed after embolization with Glubran-2. Clinical efficacy was evaluated at the 1st month [(7.57 ± 1.81 vs. 2.29 ± 0.76), 95% CI 4.257–6.314], 3rd month [(7.57 ± 1. 81 vs. 1.29 ± 0.76), 95% CI 5.257–7.315], 6th month [(7.57 ± 1. 81 vs.0.86 ± 0.69), 95% CI 5.330–8.100], and 12th month [(7.57 ± 1. 81 vs.0.42 ± 0.53), 95% CI 5.789–8.500], and complete or slight improvement of CPP after embolization was observed for all patients. The VAS scores decreased significantly from pre-intervention to post-intervention (p < 0.001). The embolization procedural parameters and VAS scores are shown in Table 2. The QOL score at 12 months was 0.19 ± 0.40. Notably, 6 young patients gave birth to healthy babies during the follow-up of Glubran-2 embolization of the ovarian vein.

Pelvic Venous Disorder (PeVD) is an underappreciated cause of CPP and disability in young women (3). Living with CPP secondary to PeVD is difficult as this condition directly affects female patients and interactions with family, friends, and general outlook on life. Thus, several treatment modalities for CPP have been proposed over time (3, 6, 17). Conservative treatment involving the use of psychotropic or non-steroidal anti-inflammatory drugs provides only short-term relief from CPP for patients awaiting further investigation or more permanent treatment and plays a minor role in sustained long-term management (18). Hysterectomy is a surgical alternative that fails to reduce CPP symptoms and has therefore been eliminated as a first option (19). Open or laparoscopic surgery to ligate insufficient veins has been proposed as a replacement treatment (13, 20, 21). To date, a consensus regarding indications for either surgery or endovascular embolization of the ovarian veins is lacking, and this topic requires further research. Endovascular embolization treatment has the advantages of minimal invasiveness and has become widely accepted during this century as one of the most effective treatment options available (3, 5–8, 15–17, 19).

Various embolic materials are used during OVE, the most common of which involve liquid sclerosing agents and metal coils, and several retrospective case series have been published on the use of these materials (7, 8, 16, 22). Kim et al. performed a case series using foam-sclerosant embolization, and the VAS significantly decreased from 7.6 ± 1.8 pre-intervention to 2.9 ± 2.8 at a follow-up of 45 ± 18 months. Laborda et al. investigated a group of patients who underwent metal-coil embolization and observed a similar significant reduction in the VAS score from 7.34 ± 0.7 pre-intervention to 0.78 ± 1.2 at a follow-up of 5 years (16, 22). Unfortunately, solid data supporting the superiority of one material over another are lacking. In the present study, a successful outcome was achieved using Glubran-2, and the VAS score decreased from 7.57 ± 1.81 pre-intervention to 0.86 ± 0.69 at the 6-month follow-up. This value corresponds to a similar efficacy but a shorter relief time and an improved QOL was noted at the 1-year follow-up. The results of this study may be attributed to the physicochemical properties of Glubran-2, which functions independently of the hemostatic capacity, such that polymerization can occur immediately upon contact with blood, leading to instant and complete occlusion of insufficient venous axes. In addition, to prevent the risk of embolic material migration, microcoils were used in 4 patients at the opening of the ovarian vein trunk following embolization with Glubran-2, and no migration events occurred in the present study. Note that 3 patients in the present study did not obtain substantial relief from symptoms and experienced CPP recurrence after initial microcoil embolization. This response may have been caused by incomplete occlusion of multiple ovarian vein trunks that occurred in 24–40% of patients (17). Finally, performing embolization using Glubran-2 as a second treatment provided CPP relief. The absence of robust supporting evidence notwithstanding, Glubran-2 appears to have the potential to treat the multiple small tributaries that are often associated with ovarian veins and may cause CPP recurrence.

Safety is an important consideration in the evaluation of OVE. However, complications from this endovascular treatment have rarely been reported in practice (1, 5, 6). One major complication of OVE is non-target vein embolization, which may be caused by using incorrect concentration ratios of glue/coils or protrusions. Another common complication is the migration of coils or glue fragments, which may be attributed to incorrect evaluation of the pelvic vein diameter due to vasospasm (1, 23). Fortunately, these complications were not observed in our study, which could be attributed to the physicochemical properties of Glubran-2 and the knowledge and experience of the clinicians in employing Glubran-2. Moreover, after OVE, no significant changes in the levels of follicle stimulating hormone, luteinizing hormone, or estradiol, which are not associated with pregnancy, were noted (1, 22, 24). Data from a previous study showed that the use of Glubran-2 to treat postpartum hemorrhage did not adversely affect uterine function while embolizing uterine arteries (25). However, there is insufficient evidence to determine whether the reproductive function was affected in our study. However, of note, 6 patients who underwent Glubran-2 embolization of the ovarian vein gave birth to healthy babies.

The coaxial catheter technique was used for all patients in this study. Before microcoils were used, a compatible 2.4-F microcatheter was coaxially positioned to ensure that the microcatheter tip tracked the dilated ovarian vein as closely as possible to enter the target varicose veins of the utero-ovarian plexus. Then, Glubran-2 was injected under withdrawal from the distal insufficient tributary branches into the proximal trunk to achieve precise occlusion of the origin of the leak. The scarcity of adverse events of instantaneous adhesion using the employed microcatheter was attributed to the hydrophilic surface coating of the microcatheter tip. Even in the event of microcatheter adhesion, the microcatheter can be drawn back safely under the protection of a Cobra catheter to prevent colloidal overflow. Note that from practical experience, the use of Glubran-2 appears to be more economical than using microcoils alone.

The present study has several limitations. First, as pain levels are typically subjective, the use of the VAS to evaluate CPP may have introduced a bias into the results, and no strict significant evaluation of QOL scores was performed. Second, considering all the inherent limitations of our relatively small and retrospective study, a multi-institutional prospective study may be required to obtain conclusive results. Third, as the aim of the present study was to evaluate the preliminary outcome of OVE with Glubran-2 for the treatment of CPP secondary to PeVD, the efficacy of Glubran-2 was not compared with conventional embolic materials, which may be necessary. Despite all the above mentioned limitations, to the best of our knowledge, the present study is the largest case series of embolization with Glubran-2 as the sole embolic material for evaluating CPP secondary to PeVD.

In conclusion, OVE with NBCA Glubran-2 is a rapid, feasible, and safe treatment for CPP secondary to PeVD. Notably, the use of the NBCA Glubran-2 appears to be a potential and attractive alternative when patients desire substantial symptom relief and the ability to continue reproducing. Glubran-2 can be used to perform complete embolization of pelvic varicosities through an ovarian vein without the risk of the migration of embolic material. Large studies are warranted to confirm the findings of the present study.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by the Institutional Review Board (IRB) of the Nanjing First Hospital, Nanjing Medical University (Nanjing, China). The patients/participants provided their written informed consent to participate in this study.

MG contributed to data collection and manuscript writing and editing. XH and BZ contributed to project development, data collection, and data analysis. JK and JG contributed to project development, data collection, data analysis, and manuscript editing. HS contributed to project development. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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