Acute and chronic effects of kisspeptin‐54 administration on GH, prolactin and TSH secretion in healthy women

Abstract

Summary Background The peptide hormone kisspeptin is essential for human reproduction, acting on the hypothalamus to stimulate gonadotrophin‐releasing hormone (GnRH) secretion. Kisspeptin is currently being evaluated as a novel therapeutic for women with infertility. However, some animal studies suggest that kisspeptin may also stimulate growth hormone (GH), prolactin and thyroid‐stimulating hormone (TSH) secretion, with implications for its safety; no previous study has investigated whether kisspeptin stimulates these pituitary hormones in humans. Aim To determine whether kisspeptin‐54 modulates GH, prolactin and TSH secretion in healthy women. Design and participants Prospective, single‐blinded, placebo‐controlled, one‐way crossover study. Five healthy women received 7 days of twice‐daily subcutaneous bolus vehicle (month 1) or 6·4 nmol/kg kisspeptin‐54 (month 2). Measurements Serum samples were analysed post hoc for GH, prolactin and TSH. Results Mean serum GH, PRL and TSH did not change during the first 4 h following kisspeptin‐54 injection when compared with vehicle. The mean frequency or amplitude of GH pulses (which influence GH function) did not change acutely following kisspeptin‐54 injection when compared with vehicle. No chronic changes in serum GH, PRL or TSH were observed over the 7‐day period of twice‐daily kisspeptin‐54 injections when compared with vehicle. Conclusion While we cannot exclude any effect of kisspeptin‐54 on GH, prolactin or TSH secretion, we observed no significant changes in these hormones at a dose of kisspeptin‐54 administration known to stimulate gonadotrophin secretion in a small study of healthy women. These data have important implications for the potential of kisspeptin to treat patients with infertility.

Stimulation of growth hormone by kisspeptin antagonists in ewes

“…In our study, we found no effect of administration of kisspeptin into the LV on GH secretion in intact ewes, which is in agreement with the reported lack of response to peripheral administration in intact cows studies (Whitlock et al 2008) and prepubertal female pigs (Lents et al 2008) but contrasts with a small GH increase reported in ewes (Whitlock et al 2010) although the immediate nutritional status may be key in this model (Foradori et al 2017). In women, both acute and chronic peripheral administration of kisspeptin-54 failed to alter GH concentrations (Jayasena et al 2014). As mentioned above, these varying and contradictory reports on the effects of kisspeptin on GH may be the result of cross signalling through the large family of RFamide receptors, especially when high doses are administered centrally.…”

“…Kisspeptin stimulated calcium influx in rat somatrotropes and secretion of GH from rat (Gutierrez-Pascual et al 2007) and bovine (Kadokawa et al 2007) pituitary cells. However, Jayasena et al (2014) found no effect of kisspeptin on GH secretion from the pituitary in vitro. In vivo studies present a complexity of findings including contradictory reports.…”

Interactions between prolactin and kisspeptin to control reproduction

“…Administration of kisspeptin-10 to culture media prepared with anterior pituitary cells extracted from 8-month-old castrated male calves increased prolactin secretion (49). However, several other studies were unable to demonstrate such effect (Table 1) (50)(51)(52)(53). In humans, for example, acute or a week of twice-daily subcutaneous (sc) administrations of kisspeptin-54, at a dose known to stimulate gonadotropin secretion, induced no effect on serum prolactin levels in healthy women (53).…”

“…However, several other studies were unable to demonstrate such effect (Table 1) (50)(51)(52)(53). In humans, for example, acute or a week of twice-daily subcutaneous (sc) administrations of kisspeptin-54, at a dose known to stimulate gonadotropin secretion, induced no effect on serum prolactin levels in healthy women (53). In fact, the ability of kisspeptin to induce prolactin secretion seems to be directly related to circulating estrogen levels, as demonstrated in rodents.…”

Kisspeptin and Prolactin

“…139 In line with these negative findings, systemic treatments with kisspeptins have been reported to cause no change in prolactin secretion in the sheep, 143 goat, 144 monkey, 145 and women. 146 There appears, therefore, that kisspeptin is not able to stimulate prolactin secretion directly from the lactotrophs in the majority of species investigated so far. It is also unclear how kisspeptin would reach the pituitary gland in significant concentrations, as this is not likely from the known neuronal populations in the hypothalamus.…”