Sensitivity to exogenous GH and reversibility of the reduced IGF-I gene expression in aging rats

Servicio de Endocrinologia, Hospital Carlos III-C.I.C., Instituto de Salud Carlos III, Sinesio Delgado 10-12, Madrid 28029, Spain.

BACKGROUND: IGF-I gene expression and IGF-I plasma concentration decline with age. A decreased sensitivity to GH has been suggested to be a contributory mechanism to this, in addition to attenuated GH secretion. OBJECTIVE: This study focuses on the sensitivity to exogenous GH and the reversibility of the reduced IGF-I gene expression in aging male rats. DESIGN: Three groups of male Wistar rats aged 3 months (young adult), 11 months (middle-aged) and 27 months (old), received recombinant human GH (rhGH) (150 microg/12 h s.c.) for seven consecutive days. RESULTS: This rhGH treatment completely reversed plasma immunoreactive IGF-I (IR-IGF-I) and hepatic IGF-I mRNA levels in 11-month-old and 27-month-old animals to the levels of the young group of animals. The sensitivity in the old group (percentage of increment after the same or lower dose of rhGH per body weight) was increased for both parameters; serum IGF-I increment: 15% in 3-month-old, 42.6% in 11-month-old and 119.1% in 27-month-old rats; and hepatic IGF-Ib mRNA increase: 45% in 3-month-old, 27.8% in 11-month-old and 64.3% in 27-month-old rats. IGF binding protein-3 (IGFBP-3) mRNA level in the liver was significantly decreased in the old group and only a partial reversion occurred in this group after rhGH treatment; the percentage of increment was also higher in the old group of rats. In extrahepatic tissues IGF-I mRNA was not significantly different in the kidney and the testis of the three groups, and the rhGH treatment produced a significant and similar increase of IGF-I mRNA level in the kidney of the three groups of rats and in the testis of the 27-month-old animals. The GHr/GHBP mRNA remained unchanged in the liver and in the kidney or the testis of the three groups, and was not influenced by the rhGH treatment. Exogenous rhGH decreased pituitary GH mRNA accumulation in a more intense manner in the old group versus control of each group: young adult, 25%; middle-aged, 41.2%; and old rats, 55%. The action of rhGH on pituitary immunoreactive GH (IR-GH) content was only significantly evident in the young group. CONCLUSIONS: These results establish that exogenous rhGH recovers the attenuated liver IGF-I gene expression and the diminished plasma IR-IGF-I in old rats to the levels of young adult animals. They also indicate that the hepatic and extrahepatic (kidney and testis) sensitivity to one established dose per weight of exogenous rhGH is not altered in old animals, or could be potentially increased in some tissues.