Regulation of somatic growth and the somatotropic axis by gonadal steroids: primary effect on insulin-like growth factor I gene expression and secretion.

Abstract

The site-specific regulation of somatic growth by sex steroids is poorly understood. The aim of the present study was to assess the influence of 17 beta-estradiol (E2) and 5 alpha-dihydrotestosterone (DHT) on somatic growth and pituitary GH and hepatic insulin-like growth factor I (IGF-I) secretion and synthesis in the adult female rat. Animals (200-250 g) underwent sham surgery or bilateral ovariectomy. Some ovariectomized (OVX) rats were given sc implants that provided almost physiological female E2 (OVX/E2) and male DHT (OVX/DHT) levels. Animals were killed 3, 7, 14, and 26 days later. Body weight gain was calculated, and pituitary GH content, pituitary GH messenger RNA (mRNA) levels, plasma GH, and circulating IGF-I concentrations were measured. Levels of hepatic IGF-I mRNA were measured at 26 days. Ovariectomy increased body weight gain (P < 0.001) in parallel with a significant elevation in plasma IGF-I (P < 0.001). Replacement of E2 markedly suppressed somatic growth (P < 0.001), plasma IGF-I concentrations (P < 0.001), and liver IGF-I gene expression (P < 0.002). However, circulating GH concentrations were high in OVX/E2 animals (P < 0.001), whereas pituitary GH stores were significantly attenuated (P < 0.05). In contrast, DHT exposure increased body weight gain (P < 0.001), circulating IGF-I concentrations (P < 0.05), and steady state hepatic IGF-I mRNA levels (P < 0.05). Pituitary GH stores were markedly elevated (P < 0.001) in DHT-treated animals, but circulating GH levels remained very low. Pituitary GH mRNA rose transiently at 7 days in OVX and OVX/E2 rats, but no consistent changes between the groups were observed thereafter. We conclude that 1) gonadal steroids have disparate effects on somatic growth in female rats, with E2 suppressing and DHT stimulating body weight gain; 2) these effects are likely to be primarily mediated at the level of IGF-I synthesis and secretion; and 3) changes in pituitary GH content and secretion probably reflect normal adjustment to changes in the intensity of IGF-I negative feedback.