Effects of long-term elevated serum levels of growth hormone on life expectancy of mice: lessons from transgenic animal models.

In this study, we characterize transgenic mice carrying fusion genes, in which the genes coding for human (h) or bovine (b) growth hormone (GH) have been put under the transcriptional control of the mouse metallothionein I (MT) or the rat phosphoenolpyruvate carboxykinase (PCK) promoter as models for investigating the long-term effects of elevated GH on life expectancy. Circulating GH concentrations ranged from 3000 to 900,000 ng/ml, from 320 to 2960 ng/ml and from 34 to 1050 ng/ml in transgenic mice belonging to the MThGH, the PCKbGH and the MTbGH groups, respectively, and were high on a short-, medium-, and long-term basis. As a consequence of excess GH in their serum, GH transgenic mice exhibited drastically reduced life span which was primarily due to severe kidney lesions (glomerular hypertrophy, sclerosis and hyalinosis associated with tubulo-interstitial changes) consistently found in these animals. Alterations of the liver observed in transgenic mice included both hepatocellular megaly and various degrees of regressive, regenerative and fibrotic changes. In older MTbGH and PCKbGH transgenic mice, hepatocellular neoplasms including both adenoma and carcinoma were frequently found in addition to non-neoplastic changes. Our study points out the suitability of GH transgenic mice to evaluate the effects of various levels of GH in long-term studies without having to take antibody production against the heterologous hormone into account. Findings in GH transgenic animals suggest that the long-term benefits and risks of GH therapy should be carefully evaluated.