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The pathogenesis of hypogonadism in cirrhosis is not completely understood. The levels of insulin-like growth factor-I (IGF-I), an anabolic factor with trophic actions on testes, are reduced in cirrhosis. This study was undertaken to evaluate whether rats with advanced cirrhosis develop hypogonadism and whether the administration of IGF-I exerts beneficial effects on testicular structure and function. Wistar rats with ascitic cirrhosis induced with CCl 4 were allocated into 2 groups (n ‫؍‬ 10, each) to receive recombinant IGF-I (20 g · kg ؊1 · d ؊1 , subcutaneously) or vehicle for 3 weeks. Healthy rats receiving vehicle were used as the control group (n ‫؍‬ 10). At baseline, both cirrhotic groups showed similar deterioration of liver function tests. Compared with controls, nontreated cirrhotic rats showed decreased serum levels of IGF-I (P F .05), reduced testicular size and weight (P F .001), and intense histopathological testicular abnormalities, including reduced tubular diameters (P F .001), loss of the germinal line (P F .001), and diminutions in cellular proliferation, spermatogenesis (P F .001), and testicular transferrin expression (P F .001). In addition, low serum testosterone (P F .01) and high serum LH (P F .01) were present in untreated cirrhotic animals. Cirrhotic rats that received IGF-I showed full recovery of testicular size and weight and of all histopathological abnormalities (P F .001 to F .01 vs. nontreated cirrhotic rats; P ‫؍‬ ns vs. controls). Serum levels of sex hormones tended to normalize. In conclusion, IGF-I deficiency may play a pathogenetic role in hypogonadism of cirrhosis. Low doses of IGF-I for a short period of time revert testicular atrophy and appear to improve hypogonadism in advanced experimental cirrhosis. (HEPATOLOGY 2000;31:592-600.)Hypogonadism is a frequent complication of advanced cirrhosis. This condition is characterized by low testosterone levels and relative hyperestrogenism and is frequently associated with loss of libido, sexual impotence and feminine body habitus in men and amenorrhea in women.

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Insulin-like growth factor I (IGF-I) bioavailability is reduced in liver cirrhosis, a condition frequently associated with malnutrition. We have analyzed in vivo absorption ofd-galactose by jejunal loops in rats with CCl4-induced liver cirrhosis and the influence of IGF-I on intestinal sugar transport in this disease. Two different study protocols were followed. In protocol 1, healthy control rats or cirrhotic rats received saline or IGF-I (2 μg ⋅ 100 g body wt−1 ⋅ day−1) for 2 wk. In protocol 2, control and cirrhotic rats received saline or IGF-I as a bolus injection of 1 μg/100 g body wt followed by continuous infusion of the same dose for 100 min. In vivod-galactose absorption was reduced in cirrhotic rats compared with healthy controls. IGF-I, as both a chronic ( protocol 1) and acute treatment ( protocol 2), was able to improve sugar transport in cirrhotic rats but had no effect on sugar absorption in healthy rats. A significant elongation of enterocyte microvilli was observed in cirrhotic animals; this alteration was totally or partially corrected by chronic or acute IGF-I administration. Our results show that in vivo jejunal sugar transport and microvilli structure are altered in liver cirrhosis and that IGF-I, among other effects, may correct these changes by modulating cytoskeletal organization in enterocytes.

Insulin-like growth factor-I (IGF-I) is produced mainly in the liver and it induces beneficial effects on the nutritional status, the liver function and oxidative hepatic damage in cirrhotic rats. The aim of this work was to analyze the effect of IGF-I on mechanisms of fibrogenesis in cirrhotic rats. Liver cirrhosis was induced by CCl(4) inhalation and phenobarbital in Wistar rats. Ten days after stopping CCl(4) administration (day 0), rats received either IGF-I (2 microg/100 g bw/day) (CI+IGF) or saline (CI) subcutaneously during 14 days. Animals were sacrificed on day 15. As control groups were used: healthy rats (CO) and healthy rats treated with IGF-I (CO+IGF). Liver histopathology, hydroxyproline content, prolyl hydroxylase activity, collagen I and III mRNA expression and the evolution of transformed Ito cells into myofibroblasts were assessed. Among the two control groups (CO+IGF), no differences were found in hydroxyproline content and these levels were lower than those found in the two cirrhotic groups. Compared with untreated cirrhotic rats, the CI+IGF-I animals showed a significant reduction in hydroxyproline content, prolyl hydroxylase activity and collagen alpha 1(I) and alpha1(III) mRNA expression. A higher number of transformed Ito cells (alpha-actin +) was observed in untreated cirrhotic animals as compared to CO and CI+IGF groups. In summary, treatment with IGF-I reduced all of the studied parameters of fibrogenesis. In conclusion, low doses of IGF-I induce in vivo an antifibrogenic effect in cirrhotic rats.

The intestine is an important target organ for insulin-like growth factor-I (IGF-I), an anabolic hormone synthesized in the liver upon growth hormone (GH) stimulation. Levels of IGF-I are reduced in cirrhosis, and altered GH/IGF-I axis may contribute to malnutrition in cirrhotic patients. Our aim was to study Na(+)-dependent jejunal transport of amino acids (L-leucine, L-proline, L-glutamic acid, and L-cysteine) in cirrhotic rats and to analyze the effect of IGF-I on this function. IGF-I or saline was administered for 2 wk to rats with CCl(4)-induced cirrhosis and saline was administered to healthy control rats. Transport of amino acids was assessed in brush-border membrane vesicles (BBMV) using (14)C- or (35)S-labeled amino acids, and the kinetic constants V(max) and K(t) were determined. Na(+)-independent uptake of L-leucine, L-proline, L-glutamic acid, and L-cysteine by BBMV was similar in all groups. Na(+)-dependent uptake of all four amino acids was significantly diminished in cirrhotic rats compared with both controls and IGF-I-treated cirrhotic rats. The latter two groups exhibited similar V(max) and K(t), whereas untreated cirrhotic rats had reduced V(max) and increased K(t) compared with normal controls and IGF-I-treated cirrhotic animals. In conclusion, the transport of all four tested amino acids by BBMV is impaired in cirrhotic rats, and low doses of IGF-I can correct this defect.

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