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- Title
Kisspeptin-54 at high doses acutely induces testicular degeneration in adult male rats via central mechanisms.
- Authors
Thompson, E. L.; Amber, V.; Stamp, G. W. H.; Patterson, M.; Curtis, A. E.; Cooke, J. H.; Appleby, G. F.; Dhillo, W. S.; Ghatei, M. A.; Bloom, S. R.; Murphy, K. G.
- 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. Mandarin translation of abstract
- Subjects
ENZYMES; RATS; GERM cells; HISTOLOGY; ANATOMY; SUBCUTANEOUS injections; ANIMAL experimentation; CELL receptors; COMPARATIVE studies; DOSE-effect relationship in pharmacology; ENDOCRINE glands; GLYCOPROTEINS; HYPOTHALAMUS; RESEARCH methodology; MEDICAL cooperation; RESEARCH; TESTIS; TIME; EVALUATION research; INTRAVENTRICULAR injections; CELL physiology
- Publication
British Journal of Pharmacology, 2009, Vol 156, Issue 4, p609
- ISSN
0007-1188
- Publication type
journal article
- DOI
10.1111/j.1476-5381.2008.00061.x