12 Chapter 1 couples with unexplained or mild male infertility. Since the publication of this network meta-analysis, a Cochrane systematic review on this topic was published in 2020 which confirmed these findings (25). A Chinese replication study of the original H2Oil study was published in 2022, also showing a similar difference in ongoing pregnancy after the use of oil-based contrast during HSG when compared to water-based contrast (29.1 versus 20.1%, RR 1.44 , 95% CI 1.15-1.81, p=0.001) as well as a shorter time to pregnancy in favour of oil-based contrast (26). Results of large studies on the effect of tubal flushing in couples with other factors of infertility such as ovulation disorders, high risk of tubal pathology and advanced female age are currently lacking. Potential mechanisms To obtain a better understanding of which patient groups will benefit from the use of oil-based flushing, it is relevant to unravel the mechanism of action of the fertility enhancing effect. Different hypotheses explaining the mechanism have been formulated (27), placing the points of action in the endometrium (28), the fallopian tube (29), and the peritoneum (30, 31). The first theory is that the oil-based contrast, derived from poppy seed oil, affects the receptivity of the endometrium through opium receptors present in endometrial cells (32). This may enhance embryo implantation. Another theory hypothesizes that tubal flushing with oil-based contrast flushes accumulated debris and mucous plugs from the proximal part of the otherwise undamaged tubes, enhancing patency and improving the tubal cilia operation (27, 29). A post-hoc analysis of the H2Oil-study showed that the benefit of oil-based contrast is especially visible in women with higher pain scores during HSG, as in women with moderate to severe pain during HSG, the ongoing pregnancy rate was higher following the use of oil-based contrast compared to the use of water-based contrast (33). In women with lower pain scores, there was no difference in ongoing pregnancy rates between oil-based or water-based contrast. These results support the hypothesis that the fertility enhancing effect is associated with a mechanical flushing effect in the fallopian tube. The reported pain is presumed to be caused by an increase in intrauterine pressure prior to dislodgment of pregnancyhindering debris from the proximal part of otherwise anatomically normal fallopian tubes. One of the several differences in the chemical and physical characteristics between the two types of contrast media might be responsible for the increased flushing potential of oil-based contrast (33). Another possible mechanism taking place in the Fallopian tubes is enhancement of ciliary activity when the oil-based contrast surrounds the cilia and reduces friction. A decrease in friction will improve the function of the cilia, generating flow inside the Fallopian tubes and facilitating transport of gametes (27).
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