Kisspeptins and the reproductive axis: potential applications to manage reproduction in farm animals

Kisspeptins (Kp) are a family of neuropeptides produced mainly by two hypothalamic neuronal cell populations. They have recently emerged as a major regulator of the gonadotropin axis and their action is located upstream of the gonadotropin-releasing hormone (GnRH) cell population. In less than 10 yr a growing body of literature has demonstrated the involvement of these peptides in most, if not all, aspects of reproductive axis maturation and function. In contrast to these abundant basic research studies, few experiments have evaluated the potential application of Kp as tools to manipulate reproduction in domestic animals. In mammals, exogenous Kp administration potently stimulates gonadotropin secretion. This action is exerted mainly, if not exclusively, through the stimulation of GnRH release. Intravenous, intraperitoneal, or subcutaneous administration of Kp induced a robust and rapid increase in plasma gonadotropins (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]). However, this stimulatory effect is of short duration. Prolonged LH and FSH release over several hours can be achieved only when Kp are given as repeated multiple bolus or as an infusion. Kp administration was used in two experimental models, ewe and pony mare, with the aim of inducing well-timed and synchronized ovulations. During the breeding season, progesterone-synchronized ewes were given an intravenous infusion of Kp starting 30 h after the removal of progesterone implants. An LH surge was induced in all Kp-treated animals within 2 h of infusion onset. In contrast, in pony mares a constant infusion of Kp for 3 d in the the late follicular phase was unable to induce synchronized ovulation. Another set of studies showed that Kp could be used to activate reproductive function in acyclic animals. Pulsatile administration of Kp in prepubertal ewe lambs was shown to activate ovarian function, leading to enhanced ovarian steroidogenesis, stimulation of LH preovulatory surge, and ovulation. In anestrous ewes, an intravenous infusion of a low dose of Kp induced an immediate and sustained release of gonadotropins, followed a few hours later by an LH surge. This hormonal pattern mimicked hormonal changes normally observed during the estrous cycle follicular phase and was associated with a high percentage of ovulating animals (80%). In summary, exogenous administration of Kp appears to be a new tool to manipulate reproduction. However, optimal doses and periods of treatment should be defined for each species, and the development of powerful analogs or long-term release formulations is necessary before large-scale applications in domestic animals could be envisaged.