Role of Reproductive Factors in Hepatocellular Carcinoma: Impact on Hepatitis B- and C-Related Risk

Abstract

Hepatocellular carcinoma (HCC) is more prevalent in men than in women. Estrogen may play some role in the development of HCC. We conducted a multicenter case-control study to evaluate the effects of reproductive factors on HCC risk, and to assess whether the association between each factor and HCC differs between hepatitis B surface antigen (HBsAg)-positive and -negative women, in which hepatitis C virus (HCV) is the major cause of HCC. The study included 218 women with HCC and 729 control women selected from nonbiological and firstdegree female relatives of patients with HCC. The risk of HCC was inversely related to the number of full-term pregnancies (FTP) (P trend ‫؍‬ .0216) and age at natural menopause (P trend ‫؍‬ .0251 among women aged 45-55 without prior surgical menopause). Oophorectomy at age <50 during premenopausal years was also a risk factor (multivariate-adjusted OR, 2.57; 95% CI, H epatocellular carcinoma (HCC) is a highly malignant disease characterized by a striking male predominance; the male-to-female ratios in the incidence of HCC range from 2 to 4 in geographically diverse populations. 1,2 This gender difference may be, at least in part, attributable to differences in exposure to lifestyle risk factors for HCC, such as alcohol consumption and cigarette smoking. 3,4 However, sex hormone and X-linked genetic factors may also be important.Estrogen receptors exist in both mammalian and human livers. [5][6][7][8] In experimental rats and mice, there is also a greater preponderance of HCC in male subjects compared with female subjects. This sex difference has been observed in various animal models, including transgenic mice expressing hepatitis B or C viral proteins. [9][10][11][12][13][14][15] In addition, ovariectomy in mice increased susceptibility to chemically induced hepatocarcinogenesis. 11,16 Although these observations may suggest some role for endogenous estrogen in the etiology of HCC in humans, these aspects received relatively scant attention. [17][18][19] Exogenous estrogen use may also be associated with the risk of HCC. Several case reports have described the occurrence of liver adenomas or focal nodular hyperplasia in women taking oral contraceptives, 20 and the possible association between use of oral contraceptives and the risk of HCC has been assessed in several studies. 3,17,[21][22][23][24][25][26][27] However, most of these studies were based on a very limited number of case subjects, and the results have been incon-

Identification of androgen response elements in the enhancer I of hepatitis B virus: A mechanism for sex disparity in chronic hepatitis B #

“…Lower estrogen activity, either caused by menopause or oophorectomy, is a risk factor for female HCC. 25 We recently showed decreased estrogen receptor-␣ protein in many female HCCs, 26 which could be caused by a mechanism regulated by microRNA-18a. 27 Moreover, Naugler et al demonstrated that estrogens could protect hepatocytes from malignant transformation via down-regulation of interleukin-6 secretion from Kupffer cells.…”

Trends in the incidence of primary liver cancer in Central Uganda, 1960–1980 and 1991–2005

“…Anecdotal evidence suggests that drinking alcohol and cigarette smoking by women have become more acceptable and increased in Uganda during recent years. Reduced parity is associated with increasing HCC risk among women (Yu et al, 2003). According to the United Nations Population Division data, total fertility rates in Uganda appear to have been stable from 1970 to 1990, with subsequent small annual declines of around 0.5% from 1990 to 2006.…”

Evaluation of Possible Carcinogenic Risk to Humans Based on Liver Tumors in Rodent Assays

“…Estrogen is a known carcinogen for humans, associated with tumors of the breast and endometrium, and possibly the ovary (Yu et al 2003). In addition, there is evidence that increased estrogen exposure can induce a small increased incidence of hepatocellular carcinomas, particularly in young women who are exposed to high-estrogen-containing contraceptive pills (IARC 1999b).…”