Sex hormones and liver cancer

Abstract

Hepatocellular carcinoma (HCC) is one of the most common malignancy in the world and it usually occurs in individuals with chronic liver disease. The neoplasm is predominant in the male gender, where it is characterized also by a worst prognosis than in females. The pathogenesis of HCC is obscure. Because of its striking male predominance, androgens have been investigated as potential factors able to induce or at least promote hepatic carcinogenesis; this hypothesis has been also supported by the ability of androgens of inducing liver neoplasms in experimental models. On the other hand, due to the fact that HCC occurs predominantly in male cirrhotics who present a characteristic hormone imbalance with a relative hyperestrogenic state, the potential role of estrogen in liver cancer has been studied as well. In this paper, the potential role of sex hormones in liver carcinogenesis has been reviewed.

Introduction

Hepatocellular carcinoma (HCC) is the fifth most common malignancy in the world. The incidence of HCC has increased in the last decades worldwide: a number between 500 000 and 1 000 000 of new cases of HCC are reported every year, and HCC is responsible for about 750 000 deaths per year (International Agency for Research on Cancer, 1997, Ikeda et al., 1993, Fattovich et al., 1997). HCC usually occurs in individuals with chronic liver disease: in fact, the risk of developing HCC per year in cirrhotics ranges from 2 to 8%, depending on the different etiologies of the underlying cirrhosis (International Agency for Research on Cancer, 1997, Ikeda et al., 1993, Fattovich et al., 1997).

The incidence of HCC varies considerably in the different areas of the world, being higher in the Eastern Asia and Sub-Saharan Africa and low in North America including USA (International Agency for Research on Cancer, 1997, Ikeda et al., 1993, Fattovich et al., 1997). The incidence in Europe is on the intermediate side, 4.0 to 12.5/100 000 and is much higher in Southern Europe, where in some areas it may reach 20 cases per 100 000 individuals (International Agency for Research on Cancer, 1997, Ikeda et al., 1993, Fattovich et al., 1997).

The pathogenesis of HCC is still poorly understood: in fact, a multi-step sequence of events leading from normal hepatic tissue to the development of cancer, possibly through some intermediate pre-cancerous lesions, has not been identified yet. What we know is that some factors are associated with an increased risk of development of the cancer. Table 1 reports the most important risk factors for HCC: as one can see, the male gender is among them. HCC, in fact, has a striking increased predominance in males, with a male to female ratio ranging from 2 to 11 to 1 in most published series (El-Serag et al., 1977). Not only males develop HCC more often than females, but once they develop the cancer, they also die more easier than females: in fact, the prognosis for the disease is more benign in females than in males and women have a better survival and a reduced recurrence of the disease after treatment (El-Serag et al., 1977).

From all these evidences, the interest of some researchers has been focused since the 80's on the possible importance of sex hormones in determining such preference for the male gender. To make things more complicated, it needs to be remembered also the unique hormonal alteration that characterizes the male individual who develops HCC. In fact, as it has been said before, HCC occurs more often in males with chronic liver disease. Being males, these individuals have been under the constant influence of androgens for their life, but due to the presence of the underlying liver disease they also present a characteristic alteration of the hormonal milieu, with a so called ‘feminization’ of their phenotype due to a relative hyperestrogenic state. As a result, both the presence of male sex hormones and the effect of the cirrhosis-induced feminization have been blamed as responsible, at least in part, for the development of HCC.