Protection of estrogens against the progression of chronic liver disease

Abstract

Hepatitis C virus infections are recognized as a major causative factor of chronic liver disease. A characteristic feature of chronic hepatitis C, alcoholic liver disease and non-alcoholic fatty liver disease is hepatic steatosis. Hepatic steatosis leads to an increase in lipid peroxidation in hepatocytes, which, in turn, activates hepatic stellate cells (HSCs). HSCs are also thought to be the primary target cells for inflammatory and oxidative stimuli, and to produce extracellular matrix components. Based on available clinical information, chronic hepatitis C appears to progress more rapidly in men than in women, and cirrhosis is predominately a disease of men and postmenopausal women. Estradiol is a potent endogenous antioxidant. Hepatic steatosis was reported to become evident in an aromatase-deficient mouse and was diminished in animals after treatment with estradiol. Our previous studies showed that estradiol suppressed hepatic fibrosis in animal models, and attenuated HSC activation by suppressing the generation of reactive oxygen species in primary cultures. Variant estrogen receptors were found to be expressed to a greater extent in male patients with chronic liver disease than in female subjects. A better understanding of the basic mechanisms underlying the gender-associated differences observed in the progression of chronic liver disease would provide valuable information relative to the search for effective antifibrogenic therapies.

Nonalcoholic Fatty Liver Disease in Menopausal Women

“…Moreover the presence of liver fibrosis was lower among the women who referred HRT use (4) . Shimizu and Ito (19) also evaluated patients with CHC and observed a beneficial effect of estradiol on the progression of chronic liver disease.…”

Características Estereológicas del Hígado de Rata (Rattus norvergicus) sometidas a Menopausia Inducida por Ovariectomía

“…Es sabido que la ovariectomía en ratas adultas produce un aumento en la ingesta y disminución de la actividad física seguida de un incremento en el peso corporal y adiposidad (Wade & Gray, 1979;Richard, 1986;Shimizu, 2003;Mayes & Watson;Lavoie et al,). Una prueba indirecta respecto a que el estradiol incrementa la oxidación de lípidos es la aparición de hígado graso y esteatosis hepática en mujeres tratadas con tamoxifeno, un potente antiestrógeno (Saibara et al, 1999).…”

“…Existen evidencias que demuestran que la disminución de la función ovárica se asocia con aumentos en los niveles séricos de citoquinas proinflamatorias como las interleucina 1 y la interleucina 6 y también el factor de necrosis tumoral alfa y que las concentraciones normales de estrógenos inhiben el aumento o la secreción espontánea de tales citoquinas (Shimizu, 2003;Codes et al, 2007b). Camargo et al (1997), señalaron que estas citoquinas promueven la regeneración hepática mediante la inducción de la proliferación de hepatocitos.…”

“…Según Shimizu (2007), las hormonas sexuales pueden desempeñar un papel importante en la progresión de enfermedades hepáticas crónicas como la esteatosis o la fibrosis. Las evidencias epidemiológica y clínica indican fuertemente que los estrógenos, en particular, el 17 b-estradiol tiene un papel preponderante en la distribución general y en el metabolismo del tejido adiposo, la deficiencia de éstos favorece el acúmulo de tejido adiposo en los tejidos, especialmente en el hígado, por la disminución de la actividad lipolítica de éste (Mayes & Watson, 2004;Lavoie et al, 2011).…”

Gender Difference in Alcoholic Liver Disease

“…Most asymptomatic carriers of HCV with persistent normal alanine aminotransferase (ALT) are females and have a good prognosis with a low risk of progression of hepatic fibrosis to the end-stage cirrhosis and its complications such as hepatocellular carcinoma (HCC) (Gholson et al, 1997;Puoti et al, 2002). The menopause is associated with accelerated progression of hepatic fibrosis, and the HCC risk is inversely related to the age at natural menopause (Shimizu, 2003;Shimizu et al, 2007a). The "female paradox" observed in patients with alcoholic liver disease in comparison with chronic viral hepatitis is based on susceptibility by females to liver damage from smaller quantities of ethanol.…”