Abstract
Gonadotropin administration during infertility treatment stimulates the growth and development of multiple ovarian follicles, yielding heterogeneous oocytes with variable capacity for fertilization, cleavage, and blastocyst formation. To determine how the intrafollicular environment affects oocyte competency, 74 individual rhesus macaque follicles were aspirated and the corresponding oocytes classified as failed to cleave, cleaved but arrested prior to blastulation, or those that formed blastocysts following in vitro fertilization. Metabolomics analysis of the follicular fluid (FF) identified 60 unique metabolites that were significantly different between embryo classifications, of which a notable increase in the intrafollicular ratio of cortisol to cortisone was observed in the blastocyst group. Immunolocalization of the glucocorticoid receptor (GR, NR3C1) revealed translocation from the cytoplasm to nucleus with oocyte maturation in vitro and, correlation to intrafollicular expression of the 11-hydroxy steroid dehydrogenases that interconvert these glucocorticoids was detected upon an ovulatory stimulus in vivo. While NR3C1 knockdown in oocytes had no effect on their maturation or fertilization, expansion of the associated cumulus granulosa cells was inhibited. Our findings indicate an important role for NR3C1 in the regulation of follicular processes via paracrine signaling. Further studies are required to define the means through which the FF cortisol:cortisone ratio determines oocyte competency.
Highlights
Gonadotropin administration during infertility treatment stimulates the growth and development of multiple ovarian follicles, yielding heterogeneous oocytes with variable capacity for fertilization, cleavage, and blastocyst formation
A higher blastocyst formation rate and lower cleavage rate was observed from the oocytes aspirated from follicles with a follicular fluid (FF) volume greater than 35 μl compared to a lower blastocyst formation rate and higher cleavage rate detected in follicles with a FF volume less than 35 μl
Circulating and intrafollicular derived factors are critical for ovulatory follicle development in humans, nonhuman primates (NHPs), and rodents[5,7,8,9,10,11,12,13,14] and the FF and its constituents are likely a reflection of the resident oocyte’s capacity for fertilization and development
Summary
Gonadotropin administration during infertility treatment stimulates the growth and development of multiple ovarian follicles, yielding heterogeneous oocytes with variable capacity for fertilization, cleavage, and blastocyst formation. The forced growth and development of multiple follicles causes a concomitant increase in heterogeneity in terms of granulosa cell and oocyte competency because the processes leading to either atresia or selection of a single dominant follicle during the natural menstrual cycle are o verridden[1,2,3,4] Such follicular heterogeneity manifests in a significant proportion of embryos arresting prior to forming blastocysts, which likely contributes to low birth rates following IVF. The mid-cycle surge of luteinizing hormone (LH), the master regulator of ovulation, triggers direct LH/chorionic gonadotropin receptor signaling and the production of autocrine or paracrine factors responsible for the resumption of meiosis and the transition from an immature germinal vesicle (GV) to a mature metaphase II (MII) o ocyte[15,16,17] This includes the synthesis and secretion of certain fatty acid-derived and steroid-based hormones, cytokines, chemokines, as well as growth factors by the cells comprising the periovulatory follicle, which in turn, regulate oocyte maturation and fertilization potential. Our findings demonstrate that an unbiased metabolomics analysis of FF provides a comprehensive assessment of the intrafollicular signaling pathways and identifies important downstream mediators in follicles containing oocytes with the greatest potential of yielding a normal term pregnancy
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