Influence of hyaluronan on endometrial receptivity and embryo attachment in sheep

Abstract

(200 words for RFD)An increasing number of reports suggests a role of hyaluronan (HA) in female reproduction and interest in its application in assisted reproduction is rising. However, there are contrasting data about the effectiveness of adding HA to the embryo-transfer medium on improving pregnancy rates. Using sheep as an experimental model, the studies reported here analysed the impact of HA infusion into the uterus on embryo attachment to uterine luminal epithelium (LE) and expression of selected markers of uterine receptivity. On Day 14 after natural mating (preattachment), uterine horns were infused with either (n = 4 each): PBS (control), HA (1 mg mL-1), HA + hyaluronidase 2 (Hyal2; 300 IU mL-1) or 4-methyl-umbelliferone (HA-synthesis inhibitor; 4MU, 1 mM). HA immunostaining on uterine sections collected on Day 17 was negative in the 4MU group and weak in the HA+Hyal2 group. In contrast to 4MU, which resulted in 100% attachment, HA infusion blocked embryo attachment in all treated animals.This was accompanied by the disappearance of mucin 1 and increased expression of osteopontin and CD44v6 in the LE of uteri with attached embryos. In conclusion, the presence of HA at the embryo-maternal interface during embryo implantation resulted in reduced endometrial receptivity and inhibited the interaction of trophoblasts with the LE, whereas clearance of HA favoured embryo attachment.3

Uterine Biophysical Profile in IUI Cycles in Relevance to Hyaluronic Acid Pessaries

“…The positive relation between HA and ER in this study agree with (9) who found that ER improve in ICSI cycle when HA pessaries used vaginally. Our finding disagrees with (10) .…”

Cytokines, growth factors and macromolecules as mediators of implantation in mammalian species

“…Despite these studies indicating beneficial roles of HA in embryo development, many other studies have failed to find a positive influence of HA inclusion in embryo transfer media on pregnancy rate [102], [111]. The result of a recent study clearly demonstrated the need for HA clearance at the foetal-maternal interface in sheep for successful implantation to occur [112]. More studies are required to clarify this ambiguity on the role of HA inclusion in embryo transfer media and implantation.…”

Regulation and roles of the hyaluronan system in mammalian reproduction

“…HYAL-2 is also expressed in trophoblast giant binucleate cells and the multinucleated syncytia of sheep placentomes commencing on day 16 of gestation (Dunlap et al 2005), coinciding with the attachment and perhaps contributing to the clearance of HA at the implantation sites. In line with these reports, inhibition of HA by the infusion of 4-MU into the sheep uterus on day 14 after natural mating enhanced embryo implantation (Marei et al 2016b). Therefore, further prospective randomised clinical trials are essential for a robust conclusion to be made concerning the potential beneficial effects of HA pathway manipulation for women undergoing embryo transfer (Loutradi et al 2008).…”