The somatotropic axis, growth hormone (GH) and insulin-like growth factor 1 (IGF-1) interact with the hypothalamic-pituitary-gonadal (HPG) axis in health and disease. GH-resistant GH receptor-disrupted (GHRKO) male mice are fertile but exhibit delayed puberty and decreases in plasma FSH levels, testicular content of LH and prolactin (PRL) receptors, while PRL levels are elevated. Because the lifespan of GHRKO mice is much greater than the lifespan of their normal siblings, it was of interest to compare age-related changes in the HPG axis in GHRKO and normal animals. Plasma IGF-1, insulin, PRL, LH, FSH, androstenedione and testosterone levels, and acute responses to GnRH and LH were measured in young (2–4 and 5–6 months of age) and old (18–19 and 23–26 months of age) male GHRKO mice and their normal siblings. Plasma IGF-1 was not detectable in GHRKO mice. Plasma PRL levels increased with age in normal mice but declined in GHRKO males and did not differ in old GHRKO and normal animals. Plasma LH responses to acute GnRH stimulation were attenuated in GHRKO mice, but increased with age only in normal mice. Plasma FSH levels were decreased in GHRKO mice regardless of age. Plasma testosterone responses to LH stimulation were attenuated in old mice regardless of genotype while plasma androstenedione responses were reduced with age only in GHRKO mice. Testicular IGF-1 mRNA levels were normal in young and increased in old GHRKO mice, whereas testicular concentrations and total IGF-1 levels were decreased in these animals. These findings indicate that GH resistance due to targeted disruption of the Ghr gene in mice leads to suppression of testicular IGF-1 levels, and modifies the effects of aging on plasma PRL levels and on responses of the pituitary and the testes to GnRH and LH stimulation. Plasma testosterone levels declined during aging in normal but not in GHRKO mice, and the age-related increase in the LH responses to exogenous GnRH was absent in GHRKO mice, perhaps reflecting a delay of aging in these remarkably long-lived animals.