Direct stimulatory effect of ghrelin on pituitary release of LH through a nitric oxide-dependent mechanism that is modulated by estrogen

Abstract

Ghrelin, a gut peptide with key actions on food intake and GH secretion, has been recently recognized as potential regulator of reproductive function. Thus, in adult female rats, ghrelin has been proven to modulate GnRH/LH secretion, with predominant inhibitory effects in vivo. We analyze herein potential direct pituitary effects of ghrelin on basal and GnRH-stimulated gonadotropin secretion in prepubertal female rats, and its interplay with ovarian inputs, nitric oxide (NO), and hypothalamic differentiation. In the experimental setting, pituitaries from intact and ovariectomized prepubertal female rats were challenged with ghrelin in vitro and LH secretion was monitored. Our results demonstrate that 1) ghrelin consistently stimulated in vitro pituitary LH secretion under different experimental conditions; 2) the sensitivity to ghrelin, expressed either as the minimal effective dose or the amplitude of the LH response, was modulated by ovarian inputs; 3) the blockade of estrogen action significantly augmented the stimulatory effect of ghrelin; 4) the stimulatory effect of ghrelin on LH secretion required proper NO synthesis; and 5) the ability of ghrelin to elicit LH secretion in vitro was preserved after alteration (masculinization) of brain sexual differentiation. Overall, our present data reinforce the concept that ghrelin participates in the control of LH secretion, with potential stimulatory actions at the pituitary level that require the presence of NO and are modulated by ovarian signals.

Ghrelin and leptin levels in relation to puberty and reproductive function in patients with beta-thalassemia

“…26 Gonadal expression of acylated-ghrelin receptors was also shown in Sertoli and Leydig cells of the testis and in follicular, luteal, surface epithelial and interstitial hilus cells of the ovary. 26 Vulliemoz et al 24 showed that ghrelin can inhibit GnRH pulse activity in ovariectomized adult monkey, while Lebrethon et al 9 reported that ghrelin reduces GnRH in the pre-pubertal period in male rats and has no effect in mature rats.…”

“…26 Gonadal expression of acylated-ghrelin receptors was also shown in Sertoli and Leydig cells of the testis and in follicular, luteal, surface epithelial and interstitial hilus cells of the ovary. 26 Vulliemoz et al 24 showed that ghrelin can inhibit GnRH pulse activity in ovariectomized adult monkey, while Lebrethon et al 9 reported that ghrelin reduces GnRH in the pre-pubertal period in male rats and has no effect in mature rats. Fernandez-Fernandez et al, 27,32 who have investigated the role of ghrelin on sexual maturation, showed that ghrelin inhibits LH The reduced levels of reproductive hormones in β-thalassemic patients could be the result of intercellular iron overload and/or disturbance of the immune system.…”

“…7,9,13,[24][25][26][27] Additionally, leptin and ghrelin showed opposing effects on pulsatile GnRH secretion. 9 Furthermore, obese children have early puberty that could be the effect of high circulating levels of leptin.…”

Testosterone Is a Strong Correlate of Ghrelin Levels in Men and Postmenopausal Women

“…Several studies suggest that ghrelin has a central (hypothalamic) inhibitory effect on gonadotropin secretion: luteinizing hormone (LH) pulsatility is suppressed by central administration of ghrelin to rats, monkeys and sheep [28], and ex vivo gonadotropin-releasing hormone (GnRH) secretion by hypothalamic explants from female rats is also inhibited by ghrelin treatment [29]. On the other hand, although ghrelin inhibits the GnRH-induced LH release by pituitary explants, it also has the opposite effect of directly stimulating both LH and follicle-stimulating hormone secretion in vitro [30]. Another level of complexity is added by the differential effects of hormones when given in a fixed or pulsatile manner.…”

Physical activity: benefit or weakness in metabolic adaptations in a mouse model of chronic food restriction?

“…Leptin was largely described to play an essential role in reproduction since db/db mice, which are deleted for leptin gene receptor, and ob/ob mice, which are deleted for leptin gene, are infertile (6,18). Moreover, upregulation of ghrelin induced a decrease in LH surge (26,53), even if the mechanisms involved are yet unknown. Chronic exposition to corticosterone inhibited LH secretion and estrous cycle and ovulation in female rodents (9,10).…”