Serum and Follicular Fluid Ghrelin Levels Negatively Reflect Human Oocyte Quality and In Vitro Embryo Development

Abstract

Adverse outcomes from assisted reproductive techniques may be related in part to the effects of metabolic dysregulation in women undergoing these procedures on oocyte quality and embryo development. Among the various molecules linking metabolic dysfunction with reproductive outcomes is a peptide called ghrelin. It has been hypothesized that ghrelin affects steroidogenesis and ovarian cellular function and may mediate the relationship between metabolism and oocyte quality. Addition of ghrelin in vitro to mice preimplantation embryos in culture prevents embryonic development. Previous studies have suggested that the relationship of ghrelin with oocyte/embryonic development may be mediated by insulin, and that the negative impact of obesity, diabetes, insulin, and other metabolic dysfunction on antiretroviral therapy outcomes may be associated with intrafollicular and serum ghrelin levels. This prospective cohort study investigated the effect of serum and follicular fluid (FF) levels of ghrelin in women undergoing assisted reproduction on ovarian steroidogenesis, oocyte quality, and embryo development. The participants were 31 normal weight women undergoing in vitro fertilization at a university-based center for assisted reproduction. Patients with polycystic ovary syndrome, hypothalamic amenorrhea, or other endocrinopathies were excluded. Successful cleavage was defined as 6 cells or more by day 3 after fertilization. After an overnight fast, serum and FF were collected from preovulatory follicles of each participant (n = 81). Levels of ghrelin, insulin, and ovarian steroids (estradiol, testosterone, and progesterone) were measured. In vitro fertilization outcomes assessed included oocyte maturity and embryo development. FF ghrelin levels correlated significantly with serum levels and were 13% lower (range: 3%–24%). Serum ghrelin levels did not correlate with the body mass index or exogenous gonadotropins. Levels correlated negatively with the cleavage rate and number of viable cleavage stage embryos. Successfully cleaved embryos and those with viable morphology were 3 to 4 times more likely to come from follicles with lower levels of ghrelin than higher levels; the odds ratios were 3.67 (95% confidence interval [CI], 1.02–13.14) and 3.46 (95% CI, 1.01–11.81), respectively. Levels of FF ghrelin were negatively correlated with FF insulin and progesterone, and positively with estradiol. FF insulin levels were 52% higher (absolute difference,1.88; 95% CI,0.31–3.45] mIU/mL) in follicles with successfully cleaved embryos compared with those that were not. These findings suggest that FF ghrelin is not produced de novo in the ovary, but seems to be a serum transudate. FF ghrelin correlates with local steroidogenesis and expression of FF insulin. The effects of serum and FF ghrelin on oocyte/embryo development may be mediated by insulin.