Kisspeptin‐54 at high doses acutely induces testicular degeneration in adult male rats via central mechanisms

Abstract

Background and purpose:The kisspeptins are critical regulators of reproduction and a therapeutic target for reproductive disease. Intracerebroventricular (i.c.v.) or peripheral injection of kisspeptin potently stimulates the hypothalamic-pituitary gonadal (HPG) axis via gonadotrophin-releasing hormone (GnRH). However, little is known regarding the effects of kisspeptin administration on testicular function. We investigated the mechanism(s) of kisspeptin-induced testicular degeneration in the rat. Experimental approach: Kisspeptin-54 (50 nmol·day -1 ) was continuously administered subcutaneously (6 h to 3 days) to male Wistar rats and reproductive hormones and testicular histology analysed. We also investigated the effects of a single subcutaneous injection of 0.5, 5 or 50 nmol kisspeptin-54. In order to determine whether the testicular degeneration observed is peripherally or centrally mediated, we investigated effects of i.c.v. injections of 5 nmol kisspeptin-54 and pre-administered a GnRH-receptor antagonist (cetrorelix) to rats peripherally treated with kisspeptin-54. Key results: Continuous subcutaneous administration of kisspeptin-54 caused testicular degeneration after only 12 h, when gonadotrophins were still markedly raised, suggesting that the degeneration is independent of the desensitization of the HPG axis to kisspeptin-54. Furthermore, a single subcutaneous injection of kisspeptin-54 caused dose-dependent testicular degeneration. Continuous kisspeptin-54 administration is thus not required to cause testicular degeneration. Pretreatment with cetrorelix blocked kisspeptin-induced testicular degeneration, and a single i.c.v. injection of kisspeptin-54 caused testicular degeneration, suggesting it is GnRH-mediated. Conclusions and implications: Kisspeptin-induced testicular degeneration appears to be centrally mediated, and result from acute hyper-stimulation of the HPG axis. Doses must be carefully considered if kisspeptin is to be used therapeutically.

Kisspeptin neurons mediate reflex ovulation in the musk shrew ( Suncus murinus )

“…The difference between sKp-29 and sKp-10 might be related to differences in degradation rate in the body. Indeed, previous studies, including ours, demonstrated that rKp-52 or hKp-54 shows much higher induction of LH release than 33) and suggested that rKp-52 and hKp-54 are more stable than Kp-10. This notion is in line with the current results demonstrating that administration (5 nmol) of two stable GPR54 agonists consisting of five amino acids, FTM080 and FTM145, induced ovulation in musk shrews, but the same dose of sKp-10 or rKp-10 did not.…”

Kisspeptin modulates fertilization capacity of mouse spermatozoa

“…However, continuous s.c. administration or single high dose of kisspeptin 54 causes testicular degeneration in rats (Thompson et al 2006, Ramzan & Qureshi 2011. Pretreatment with the GnRH receptor antagonist cetrorelix blocks kisspeptin-induced testicular degeneration, suggesting a GnRH-mediated process through acute hyperstimulation of the HPG axis and not a direct effect of kisspeptin on testes (Thompson et al 2009). …”

Rola sygnalizacji kisspeptyny w osi podwzgórze–przysadka–nadnercza — aktualna perspektywa

“…Evidence from animal studies has shown that kisspeptins exhibit pulsatile secretion within the hypothalamus [108] and continuous Kp-10 stimulation leads to desensitisation of kisspeptin receptors as shown by an initial rise in LH levels followed by a rapid drop to baseline levels [118][119][120][121]. But when Kp-10 was given intermittently as twice daily injections it resulted in chronic stimulation of HPG-axis in both rats and monkeys [122,123].…”