ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2006) 12 P92

Continuous administration of kisspeptin-54 leads to desensitisation of the hypothalamo-pituitary-gonadal axis and testicular degeneration

GF Appleby, EL Thompson, KG Murphy, M Patterson, GA Bewick, GWH Stamp, JF Todd, MA Ghatei & SR Bloom

Imperial College, London, United Kingdom.

Kisspeptin-54 is a neuropeptide encoded by the Kiss-1 gene with an important role in the regulation of reproduction and puberty. Acute peripheral or intra-hypothalamic administration of kisspeptin-54 potently stimulates the hypothalamo-pituitary-gonadal (HPG) axis via hypothalamic gonadotrophin releasing hormone (GnRH) neurons. However, the effects of chronic continuous kisspeptin administration are poorly characterised. Our studies investigated the effects of chronic, continuous subcutaneous kisspeptin administration on the HPG axis and testicular physiology. Adult male rats received Kisspeptin-54 (50 nmol/day) via subcutaneous osmotic pumps for 1, 2 and 3 days. In a second experiment, the effects of the same protocol at 6, 12 and 24 hours, and a single acute subcutaneous bolus of 50 nmol kisspeptin 54 at 24 hours were investigated. Circulating levels of luteinising hormone (LH), and testosterone were increased compared to saline controls following 1 day of continuous kisspeptin administration. These stimulatory effects were lost following 2 days of continuous kisspeptin administration. Further investigation demonstrated that following 6 hours of chronic kisspeptin administration, plasma LH, follicle stimulating hormone (FSH) and testosterone were elevated. Although this effect was still significant at 12 and 24 hours, the magnitude of the response was diminished. Acute administration of kisspeptin-54 did not result in raised LH, FSH or testosterone at 24 hours post-injection. Testicular histology revealed minor testicular degeneration following 6 hours continuous kisspeptin administration, with more advanced degeneration visible at 12 hours and later time points. Chronic continuous kisspeptin administration therefore initially stimulates the HPG axis. The HPG axis subsequently becomes desensitised to this stimulatory effect. Following 2 days continuous administration, 50 nmol/day kisspeptin-54 no longer stimulates the HPG axis. This desensitisation occurs earlier than that observed following GnRH agonist administration. Further investigation is required to determine whether the effects of kisspeptin administration on testicular histology are direct or mediated via the HPG axis.

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