Testosterone effect on growth and growth mediators of the GH-IGF-I axis in the liver and epiphyseal growth plate of juvenile rats

Abstract

Several studies have suggested that testosterone may have a direct, GH-independent effect on growth. In order to assess possible mechanism(s) whereby testosterone exerts its growth-promoting effect, we evaluated its effect on growth mediators of the GH-IGF-I axis, in both the liver and the epiphyseal growth plate (EGP). Testosterone was administered to peripubertal rats and the responses of mRNA of GH receptor, IGF-I, IGF-I receptor and IGF-binding proteins-1 and -3 (IGFBP-1 and IGFBP-3) as well as circulating IGF-I were evaluated in two time-related models: over 12 h after a single injection (short-term study) and 10 days after continuous administration (long-term study). Rats in the short-term study were castrated and were killed 1, 4, 6 and 12 h post injection. Rats in the long-term study were divided into two groups: castrated vs castrated and hypophysectomized, in order to assess the effect of testosterone in the presence and absence of GH. mRNA levels were determined by RNase protection assay, and serum IGF-I by RIA.Testosterone enhanced weight gain in the rats treated for 10 days, a change that was similar in the presence or absence of GH. This effect was relatively small, however, by comparison with the total weight gained without testosterone. Testosterone had no effect on hepatic IGF-I mRNA abundance but induced a reduction in circulating IGF-I levels, in both the short-and long-term study. Testosterone had no effect on hepatic GH receptor and IGFBP-3 mRNA levels but resulted in a transient, short-term elevation in IGFBP-1 mRNA levels that was maximal 4 h post injection.In the EGP, neither testosterone administration nor hypophysectomy had any effect on IGF-I and IGF-I receptor mRNA levels. However, testosterone increased GH receptor mRNA abundance after 10 days of continuous administration in hypophysectomized rats only.These data suggest that the effect of testosterone on growth (as assessed by weight gain) is small and is not mediated by changes in hepatic gene expression of IGF-I, IGF-I receptor, IGFBP-1, IGFBP-3 or circulating IGF-I. At the EGP, the testosterone effect on linear growth is not mediated through changes in mRNA abundance of IGF-I and IGF-I receptor. The small but significant elevation of GH receptor mRNA levels in hypophysectomized rats may suggest a testosterone-mediated augmentation of a GH effect at the target organ.

Cardiac hypertrophy and IGF-1 response to testosterone propionate treatment in trained male rats

“…Testosterone (T enanthate; 300 mg im, each week) administration increased serum IGF-1 concentrations in healthy men after 6 weeks of treatment; however, treatment with exogenous steroids (nandrolone decanoate; 300 mg im, each week) did not change serum levels of IGF-1 but did decrease the level of the serum IGF-binding protein-3, potentially increasing the level of bioavailable IGF-1 in the nandrolone subjects [21]. In contrast to these studies in humans, testosterone administration to juvenile rats, has been reported to significantly decrease circulating levels of IGF-1 [15]. We did not analyzed the serum IGF-1 levels, however, previous results confirmed that there was a negative correlation between TT levels in rats treated with high doses of testosterone and serum IGF-1 [15].…”

“…The results of in vivo and in vitro experiments indicate that insulin-like growth factor (IGF)-1 is an important growth factor which, by its receptors, mediates cardiac growth in a PI-3K dependent manner [12,13]. However, the precise role of IGF-1 in the regulation of cardiac structure under both physiological stress and the direct effect of testosterone remains debatable [14,15,16].…”

“…These effects are modulated through the interaction of hormonal concentrations and training overload. IGF-1 secretion is associated with an increase in plasma concentrations of growth hormone (GH) [15,20] and sex steroids [21,22]. Cardiomyocytes express androgen receptors which, when activated, modulate gene expression in the cells [23].…”

“…It has been reported that chronic anabolic T treatment led to a specific physiologic pattern of myocardial hypertrophy with a significant increase in left ventricle (LV) weight, with an upregulation in alpha/beta myosin heavy chain(MHC), and an increase in IGF-1 expression [22,24,25]. Several lines of evidence, however, have suggested that testosterone induced a reduction in circulating IGF-1 levels and may have a direct, IGF-1 and GH-independent effect on growth [15].…”

Sex steroids and the GH axis: Implications for the management of hypopituitarism

“…A similar effect occurs in the growth plates of hypophysectomized rats [61]. Testosterone, therefore, modulates the peripheral action of GH on the growth plate and liver by enhancing GHR expression.…”