Ghrelin Inhibits Steroid Biosynthesis by Cultured Granulosa-Lutein Cells

Abstract

Context:Growing evidence indicates that ghrelin may participate in the regulation of different aspects of reproductive function. The genes encoding for this peptide and its receptor are expressed in the human ovary, but their functional role is still unknown. Objective:The aim of our study was to assess whether ghrelin has any effect on steroid synthesis by human granulosa-lutein cells and to identify the receptor isoform through which this potential effect is exerted.Design, Patients, and Methods: Thirty-five women with spontaneous ovulatory cycles undergoing in vitro fertilization for infertility due to uni-or bilateral tubal impatency or male factor were studied. Granulosa-lutein cells obtained from follicular fluid were incubated with increasing amounts of human acylated ghrelin (10 Ϫ11 to 10 Ϫ7 mol/liter) either alone or together with a 1:500 concentration of a specific anti-ghrelin receptor antibody [GH secretagogue receptor 1a (GHS-R1a)]. Culture media were tested for estradiol (E 2 ) and progesterone (P 4 ). The expression of GHS-R1a and GHS-R1b in human granulosa-lutein cells was also studied by real-time quantitative PCR.Results: E 2 and P 4 concentrations in the culture media were significantly reduced by ghrelin in a dose-dependent fashion. The maximal decrease in E 2 (25%) and P 4 (20%) media concentrations was obtained with the 10 Ϫ7 and 10 Ϫ8 mol/liter ghrelin concentrations, respectively. The inhibitory effect of all ghrelin concentrations used was antagonized by the specific anti-ghrelin receptor-1a antibody added to the culture media and not by the specific anti-ghrelin receptor-1b antibody. Both 1a and 1b isoforms of the GHS-R were expressed in human granulosa-lutein cells, with the latter exceeding the former's expression (GHS-R1b/GHS-R1a ratio, 143.23 Ϯ 28.15). Conclusions:Ghrelin exerts an inhibitory effect on granulosa-lutein cells steroidogenesis by acting through its functional GHS-R1a. This suggests that ghrelin may serve an autocrine-paracrine role in the control of gonadal function and be part of a network of molecular signals responsible for the coordinated control of energy homeostasis and reproduction.

The Effects of Ovariectomy on Ghrelin Expression in the Rat Uterus

“…A similar expression pattern has been found in the human ovary, where hilus interstitial cells and young and mature corpus lutei were found to be ghrelinimmunoreactive [30]. Ghrelin inhibits estradiol and progesterone secretion from granulose cells of the human ovary, but this effect was blocked in the presence of a ghrelin receptor antagonist [31].…”

Association of serum and follicular fluid leptin and ghrelin levels with in vitro fertilization success

“…Also, it was suggested that Ghrelin might have an autocrine-paracrine role in the ovary. Thus it was shown that ghrelin exerted an inhibitory effect on granulosa-lutein cells steroidogenesis by acting through its functional receptor GHs-R1a [32]. Ghrelin was also shown to inhibit the development of mouse preimplantation embryos in vitro [33].…”

Ghrelin and reproductive disorders

“…Recently, the expression of the GHSR-1a and 1b isoforms has been demonstrated in human granulosa-luteal cells (Viani et al, 2008), and in an in vitro model, it has been reported that, through this receptor, ghrelin significantly inhibited, in a dose-dependent manner, estradiol and progesterone secretion by granulosa-luteal cells. Intriguingly, it could therefore be suggested that such an effect may contribute to suppression of the reproductive axis at times of food deprivation, when limited resources are allocated to major physiological processes.…”