Human ghrelin decreases pituitary response to GnRH in superovulated ewes

In addition to its metabolic role, ghrelin has been found to suppress luteinizing hormone secretion in many species acting mainly at the hypothalamic level. The objectives of the present study were to test the hypothesis that besides its effects on the hypothalamic level, ghrelin exerts a direct action on the pituitary. Twelve cycling ewes were synchronized, using progestagen intravaginal sponges and superovulated using eCG. At the time of sponge withdrawal, animals were allocated into two groups, ghrelin-treated (Gh) and control. Two days after the sponge removal, GnRH was given to synchronize ovulations. Simultaneously with GnRH treatment, animals of the Gh group received the first of four treatments of acylated human ghrelin at a dose of 6 μg/kg body weight iv; three additional treatments of ghrelin iv were given every 15 minutes thereafter. Control animals received saline iv. Blood samples were collected before challenge (-30 and 0 minutes) and at 30, 60, 75, 90, 105, 120, 135, 150, and 180 minutes after GnRH treatment, and were analyzed for LH, FSH, estradiol, progesterone, insulin, and insulin-like growth factor-I concentrations. Ghrelin treatment attenuated GnRH-induced a preovulatory surge of both gonadotrophins, with the effect being greater for LH. No difference was detected for insulin, estradiol, and progesterone concentrations, and insulin-like growth factor-I levels were increased in the Gh group. Our results imply that in sheep, ghrelin conducts specific regulatory effects on the GnRH/LH axis, and provide for the first time strong evidence that besides its central action, ghrelin might regulate gonadotrophin release acting at the pituitary level.