Hyaluronan (HA) is a non-sulphated glycosaminoglycan polymer naturally occurring in many tissues and fluids of mammals, including the reproductive system. Its biosynthesis by HA synthase (HAS1-3) and catabolism by hyaluronidases (HYALs) are affected by ovarian steroid hormones. Depending upon its molecular size, HA functions both as a structural component of tissues in the form of high-molecular-weight HA or as a signalling molecule in the form of small HA molecules or HA fragments with effects mediated through interaction with its specific cell-membrane receptors. HA is produced by oocytes and embryos and in various segments of the reproductive system. This review provides information about the expression and function of members of the HA system, including HAS, HYALs and HA receptors. We examine their role in various processes from folliculogenesis through oocyte maturation, fertilisation and early embryo development, to pregnancy and cervical dilation, as well as its application in assisted reproduction technologies. Particular emphasis has been placed upon the role of the HA system in pre-implantation embryo development and embryo implantation, for which we propose a hypothetical sequential model. Reproduction (2017) 153 R43-R58

In this study, we investigated steroid regulation of the hyaluronan (HA) system in ovine endometrium including HA synthases (HAS), hyaluronidases, and HA receptor-CD44 using 30 adult Welsh Mountain ewes. Eight ewes were kept intact and synchronized to estrous (day 0). Intact ewes were killed on day 9 (luteal phase; LUT; nZ5) and day 16 (follicular phase; FOL; nZ3). The remaining ewes (nZ22) were ovariectomized and then treated (i.m.) with vehicle (nZ6) or progesterone (nZ8) for 10 days, or estrogen and progesterone for 3 days followed by 7 days of progesterone alone (nZ8). Estradiol and progesterone concentrations in plasma correlated with the stage of estrous or steroid treatment. Our results showed trends (P!0.1) and statistically significant effects (P!0.05, by t-test) indicating that LUT had lower HAS1 and HAS2 and higher HAS3 and CD44 mRNA expression compared with FOL. This was reflected in immunostaining of the corresponding HAS proteins. Similarly, in ovariectomized ewes, progesterone decreased HAS1 and HAS2 and increased HAS3 and CD44, whereas estradiol tended to increase HAS2 and decrease CD44. Sometimes, HAS mRNA expression did not follow the same trend observed in the intact animals or the protein expression. HA and its associated genes and receptors were regulated by the steroids. In conclusion, these results show that the level of HA production and the molecular weight of HA in the endometrium are regulated by ovarian steroids through differential expression of different HAS both at the gene and at the protein levels.

Implantation is one of the most critical steps in mammalian reproduction and implantation failure constitutes a major cause of infertility in both animals and humans. The mechanism of implantation is exclusively under the control of ovarian steroids progesterone and oestrogen whose actions are mediated in a complex phenomenon that involves a number of cytokines and growth factors. According to a plethora of literature on implantation in mammalian species, prominent of these cytokines and growth factor playing crucial roles in implantation include integrin, osteopontin, integrin, insulin-like growth factor and leukaemia inhibitory factor. Others are cluster domain 44, hyaluronan system and many non-adhesive molecules such as glycoprotein mucin 1. In this review, the specific roles played by these molecules are expatiated. Generally, they function as adhesive molecules that facilitate attachment of ligands/proteins on the trophectoderm to their respective receptors on endometrial luminal epithelia or vice versa. Sometimes, they also function as signalling molecules that enhance communication between implanting blastocyst and receptive endometrium. This is of particular importance in embryo culture and embryo transfer where in vitro derived blastocyst unlike the in vivo condition, is not exposed to these substances and hence, their absence may be partly responsible for the low implantation rate observed in the surrogate. Appreciation of the roles played by these cytokines, growth factors and molecules as revealed in this review will spur further research on these topics, facilitate their inclusion in embryo culture media (if positively required) and are considered as vital aspect while developing strategies to improve fertility.

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