ORIGINAL ARTICLE Hypothalamic Expression of Human Growth Hormone Induces Post-Pubertal Hypergonadotrophism in Male Transgenic Growth Retarded Rats J. S. Davies,* N. M. Thompson,* H. C. Christian,   L. Pinilla, à F. J. P. Ebling, § M. Tena-Sempere à and T. Wells* *School of Biosciences, Cardiff University, Cardiff, UK.   Laboratory for Cellular Endocrinology, University of Oxford, Department of Human Anatomy and Genetics, Oxford, UK. à Physiology Section, Faculty of Medicine, University of Cordoba, Cordoba, Spain. §Queen’s Medical Centre, University of Nottingham, Nottingham, UK. The postnatal maturation of the hypothalamo-pituitary-growth hor- mone (HPGH) and hypothalamo-pituitary-gonadal (HPG) axes occurs in close temporal proximity. In addition to being choreo- graphed by common homeostatic cues, the development and acti- vation of these axes may also be influenced by significant reciprocal interaction. For example, it is well established that the gonadal steroids influence both the initiation and sustained activity of the HPGH axis (1, 2), and, although less well characterised, there is now growing evidence that the HPGH axis may influence the timing of puberty and the maintenance of fertility (3–5). The net effect of growth hormone (GH) on the HPG axis appears to be positive because isolated GH-deficiency or GH-insensitivity are associated with delayed puberty and impaired fertility (6–9). The widespread distribution of GH receptors throughout the HPG axis Journal of Neuroendocrinology Correspondence to: Dr Tim Wells, School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3US, UK. e-mail: wellst@cardiff.ac.uk. Growth hormone (GH) is known to regulate peripheral components of the hypothalamo-pituitary gonadal (HPG) axis, but it remains unclear whether GH exerts a significant influence on the activity of the hypothalamo-pituitary components of the HPG axis. In this study, we investigated the development of HPG axis function in the male transgenic growth retarded (Tgr) rat, a model of moderate systemic GH deficiency caused by hypothalamic expression of human (h)GH. Impaired postnatal somatotroph expansion and moderate GH deficiency in male Tgr rats were accompanied by a two- to three-fold increase in pituitary gonadotrophin content, but without a significant change in the pituitary gonadotroph population. A three- to nine-fold elevation in basal circulating luteinising hormone concentration was seen in postpubertal Tgr rats, with a smaller increase in follicle-stimulating hormone. Despite this hypergonadotrophism, there was no corresponding increase in steroidogenic (circulating testosterone and seminal vesicle weights) or gametogenic (spermatozoa counts in seminiferous tubules) activity in the postpubertal Tgr testis. Following puberty, the plasma leptin concentration also became progressively elevated in Tgr males. Circulating gonadotrophin and leptin levels were normalised in Tgr rats by peripheral physiological replacement of rat GH, but plasma testosterone concentration was unaffected. These results confirm that hGH exerts a positive influence on the central control of gonadotro- phin secretion in the Tgr rat, but the absence of a corresponding elevation in the steroidogenic or gametogenic function of the Tgr testis implies that the peripheral GH ⁄ insulin-like growth fac- tor I axis may also exert a permissive influence on testicular function. The relative contribution of somatogenic and lactogenic mechanisms and the potential influence of elevated leptin and decreased sensitivity to androgen feedback to the development of postpubertal hypergonadotro- phism in Tgr males remain to be determined. Key words: hypothalamo-pituitary-gonadal axis, growth hormone, growth hormone deficiency, gonadotrophins, testis. doi: 10.1111/j.1365-2826.2006.01467.x Journal of Neuroendocrinology 18, 719–731 ª 2006 The Authors. Journal Compilation ª 2006 Blackwell Publishing Ltd