Gonadotrophin-releasing hormone: Physiological significance and relevance to cancer

Abstract

Gonadotrophin releasing hormone (GnRH) is a decapeptide released by the hypothalamus. The binding of the peptide to pituitary receptors leads to the activation of second messenger systems. The physiological outcome of the exposure of pituitary cells to GnRH is the release of luteinising hormone (LH) and follicle-stimulating hormone (FSH). Continued exposure of these receptors to high concentrations of the peptide desensitises the receptor, thus inhibiting the release of gonadotrophins. This paradoxical effect has proved to be beneficial in the clinic where long-acting and enzyme-resistant analogues are used to inhibit the pituitary-gonadal axis, for example in the treatment of advanced prostatic cancer. In addition GnRH-analogues may affect tumour cells directly as observed in vitro. These direct effects have been described as inhibitory but recent data suggests that low concentrations of GnRH-analogues may stimulate short term growth of prostatic cancer cells in vitro. GnRH shares many other common characteristics with peptide growth factors, including common second messenger systems and receptor desensitisation on prolonged exposure to the ligand. It is possible that the direct inhibitory effects of GnRH-analogues are mediated through the desensitisation of tumour GnRH receptors, as suggested by recent observations. The nature and mechanism of the direct anti-tumour effect is important to understand and to promote the therapeutic efficacy of GnRH-analogues in the clinic.