Maternal Ghrelin Deficiency Compromises Reproduction in Female Progeny through Altered Uterine Developmental Programming

Abstract

Ghrelin has a well-known role in the regulation of appetite, satiety, energy metabolism, and reproduction; however ghrelin has not been implicated in reproductive tract development. We examined the effect of ghrelin deficiency on the developmental programming of female fertility. We observed that female wild-type mice born of ghrelin heterozygote dams (i.e. exposed in utero to ghrelin deficiency) had diminished fertility and produced smaller litters. We demonstrate that exposure to in utero ghrelin deficiency led to altered developmental programming of the reproductive tract. The number of ovarian follicles, corpora lutea, and embryos produced were identical in both exposed and unexposed mice. However wild-type embryos transferred to uteri of mice exposed to in utero ghrelin deficiency had a 60% reduction in the rate of embryo implantation compared with those transferred to wild-type unexposed uteri. We identified significant alterations in the uterine expression of four genes critical for implantation and a defect in uterine endometrial proliferation. Taken together, these results demonstrate that the mechanism of subfertility was abnormal endometrial function. In utero exposure to decreased levels of ghrelin led to defects in developmental programming of the uterus and subsequent subfertility in wild-type offspring.

The Role of Intragestational Ghrelin on Postnatal Development and Reproductive Programming in Mice

“…It is interesting that a similar tendency was observed in adult females exposed to intragestational GHRL imbalances. A remarkable study by Martin et al (2011) demonstrated a significantly lower implantation index in female mice exposed to intragestational GHRL deficiency (similar to our Ant treatment), explained by impaired endometrial function. As in our study, they did not find any alterations in ovarian follicles or corpora lutea (Martin et al 2011).…”

“…Therefore, the information obtained from these studies about the physiological role of GHRL during pregnancy is limited. Moreover, to our knowledge, there is only one study of the effects of maternal GHRL deficiency (comparing homozygote with heterozygote dams) on reproductive foetal programming of female offspring (Martin et al 2011).…”

Plasma Ghrelin Concentrations Were Altered with Oestrous Cycle Stage and Increasing Age in Reproductively Competent Wistar Females

“…For example, a study using ghrelin heterozygous mice reported that a systemic low level of maternal ghrelin appeared to have an adverse effect on the uterine programming of their wild-type female offspring, causing subnormal fertility rates through reduced implantation, despite normal ovarian function and embryo production [19]. These authors suggested that their findings could have serious implications for the fertility of women born to obese mothers who would have had blunted ghrelin levels due to their obesity.…”

Ghrelin: Ghrelin as a Regulatory Peptide in Growth Hormone Secretion

“…Ghrelin-immunoreactive neurons are present in few regions of the brain like the arcuate and the ventromedial nucleus of the hypothalamus, cerebellum and brainstem [12,[18][19][20]. Ghrelin is also present in placenta along GH, GHRH, somatostatin and insulin-like growth factor 1 (IGF1) which shows that it is also involved in fetal growth [21].…”