Direct associations between ovarian retinoid levels, oocyte fertilization
and embryo quality in women undergoing in vitro fertilization
Juanjuan Wu, Samuel A. Pauli, Monica W. Best, Neil Sidell
Department of Gynecology and Obstetrics, Emory University, School of Medicine,1639 Pierce Drive, Atlanta, GA 30322, USA.
Although the introduction of in vitro fertilization (IVF), has revolutionized the treatment of infertility, assisted human reproduction remains an inefficient process with the majority of oocytes failing to produce a live birth. Amongthe many factors influencingIVF efficiency, oocyte developmentplays a critical role in determining reproductive outcomes.To this end, oocyte maturationis significantly affected by the surrounding micronutrient environment of the ovarian follicle. One such important group of micronutrients are the retinoids, a class of compounds that are chemically related to vitamin A (retinol [ROL]). Although high levels of retinoids can be teratogenic, ROL and its biologically active metabolite, all-trans retinoic acid (ATRA), are essential for a number of reproductive processes. However, there is a paucity of information regarding their roles in ovarian folliculogenesis, oocyte maturation, and early embryogenesis. Given the importance of retinoids that have been demonstrated in a variety of reproductionanimal models and the ability of retinoids to modulate gene transcription, we designed a prospective observational study to determine the concentrations of retinoids in the peripheral plasma (PP) and follicular fluid (FF) of women undergoing IVF. Because ATRA is essential to oogenesis, we hypothesized that this retinoid affects early embryo development and therefore sought to assess whether FF levels of ATRA might correlate with embryo quality.Along with these evaluations, wealso quantified retinoid levels in human cumulus granulosa cells (CGC)and investigated the potential relationship between CGC ATRA levels and successful oocyte fertilization.Our results demonstrated thathigh FF ATRA concentrations at the time of oocyte retrieval were associated with oocytes giving rise to higher quality (grade I) embryos with IVF. We then showed thatpatients yielding the highest percentage of successfully fertilized oocytes had significantly higher mean levels of ATRA in their CGC. Our analysis did not show significant differences in retinol levels between the groups supporting the contention that increased retinoid biosynthesis, rather than uptake of the retinol precursor, may be important for influencing oocyte quality. We also determined that ATRA is actively produced and secreted from CGC, which suggests that the concentrations determined in follicular fluid at the time of oocyte retrieval may, at least partially, reflect retinoid biosynthesis by CGC.Thus, high FF ATRA levels associated with grade I embryos appears to be a consequence of efficient retinoid metabolic activity in the follicle’s CGC which is important for production of high quality oocytes. Taken together, these results present a mechanism by which retinoid metabolism in CGC may play a dynamic role in oogenesis and successful fertilization. Along with an increased understanding of the role of retinoids in ovarian follicle processes, this information may lead to a new appreciation of the cause(s) of impaired oocyte development in some women.