Suppressive effect of oestradiol on chemical hepatocarcinogenesis in rats

Shimizu, Ikuya; Yasuda, Mitsuhiro; Mizobuchi, Y; Ma, Yi; Liu, F.; Shiba, Masahiro; Horie, Takeshi; Ito, Shuhei

doi:10.1097/00042737-199804000-00019

Cited by 15 publications

(19 citation statements)

References 8 publications

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“…The presence of a B allele at Hcs4 locus influences positively lesion volume (15). Our results reveal a sex dimorphism in HCC development in the resistant BN rats, analogous to that previously described in susceptible rat strains (5,6). These findings also show that the presence of homozygous B alleles, between D16Mit5 and D16Rat75 at RNO16 in an isogenic FF background, is associated, in male congenic F344.BN-Hcs4 rats, with a susceptibility to hepatocarcinogenesis comparable to that of male F344 rats and, in female congenics, with a resistance comparable to that of female BN rats.…”

Section: Discussionsupporting

confidence: 87%

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Mapping a Sex Hormone–Sensitive Gene Determining Female Resistance to Liver Carcinogenesis in a Congenic F344.BN-Hcs4 Rat

Miglio

Virdis²,

Calvisi³

et al. 2006

Cancer Research

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Hepatocellular carcinoma (HCC) is prevalent in human and rodent males. Hepatocarcinogenesis is controlled by various genes in susceptible F344 and resistant Brown Norway (BN) rats. B alleles at Hcs4 locus, on RNO16, control neoplastic nodule volume. We constructed the F344.BN-Hcs4 recombinant congenic strain (RCS) by introgressing a 4.41-cM portion of Hcs4 from BN strain in an isogenic F344 background. Preneoplastic and neoplastic lesions were induced by the ''resistant hepatocyte'' protocol. Eight weeks after initiation, lesion volume and positivity for proliferating cell nuclear antigen (PCNA) were much higher in lesions of F344 than BN rats of both sexes. These variables were lower in females than in males. Lesion volume and PCNA values of male RCS were similar to those of F344 rats, but in females corresponded to those of BN females. Carcinomatous nodules and HCC developed at 32 and 60 weeks, respectively, in male F344 and congenics and, rarely, in F344 females. BN and congenic females developed only eosinophilic/clear cells nodules. Gonadectomy of congenic males, followed by B-estradiol administration, caused a decrease in Ar expression, an increase in Er-a expression, and development of preneoplastic lesions comparable to those from BN females. Administration of testosterone to gonadectomized females led to Ar increase and development of preneoplastic lesions as in F344 males. This indicates a role of homozygous B alleles at Hcs4 in the determination of phenotypic patterns of female RCS and presence at Hcs4 locus of a high penetrance gene(s), activated by estrogens and inhibited/unaffected by testosterone, conferring resistance to females in which the B alleles provide higher resistance. (Cancer Res 2006; 66(21): 10384-90)

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Section: Discussionsupporting

confidence: 87%

“…Endocrine ablation studies showed enhancement of hepatocarcinogenesis by testosterone and inhibition by ovarian hormones (4)(5)(6). These effects depend on functional specific receptors (7,8).…”

Section: Introductionmentioning

confidence: 99%

Mapping a Sex Hormone–Sensitive Gene Determining Female Resistance to Liver Carcinogenesis in a Congenic F344.BN-Hcs4 Rat

Miglio

Virdis²,

Calvisi³

et al. 2006

Cancer Research

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“…treatment effect of various synthetic forms of estrogens on hepatocarcinogenesis in some animal models, 16,28,32,33 but is opposite to others. [29][30][31] However, it should be noted that oral contraceptive steroids administered in animal studies that suggested estrogens as promoters of hepatocarcinogenesis were usually given at a very high dose (between 6 to 200 times the human dose).…”

Section: Discussionmentioning

confidence: 90%

“…Moreover, the effect of long-term treatment with estrogen on hepatocarcinogenesis in animals is controversial. 16,[28][29][30][31][32][33] This study reports on associations between reproductive events and exogenous estrogen use and HCC, as observed in a multicenter case-control study of women in Taiwan, where HCC is endemic. 1,2 An attempt is made to assess the heterogeneity of associations for the risk of HCC in relation to chronic infection with hepatitis B virus (HBV) and hepatitis C virus (HCV), which are the most important determinants of the disease.…”

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confidence: 99%

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

Chang

et al. 2003

Hepatology

106

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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-

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“…It has been reported that sex hormones such as estrogen and immune response play an important role in hepatocarcinogenesis (44,45). Since the levels of sex hormones decrease in ageing women, the risk of the incidence of HCC in elderly females increases.…”

Section: ------------------------------------------------------------mentioning

confidence: 99%

HCC develops even in the early stage of chronic liver disease in elderly patients with HCV infection

Takata

Kuromatsu²,

Ando³

et al. 2010

Int J Mol Med

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Abstract. In recent years, the number of elderly patients with hepatocellular carcinoma (HCC) has been increasing. The aim of this study was to compare the liver function and the background factors of HCC patients with hepatitis C virus (HCV) infection by generation and to examine the characteristics of this disease in the elderly. A total of 1096 patients (776 men and 320 women) diagnosed with HCVrelated HCC at our institution from 1995 to 2006 were divided into 4 groups as follows: D group, 75 years of age or older; C group, 65-74 years of age; B group, 55-64 years of age; A group, 54 years of age or younger, and the liver function and other clinical characteristics were compared among these 4 groups. The average age at initial diagnosis of HCVrelated HCC was 66.9 years of age. The A, B, C and D groups were comprised of 87, 363, 514 and 132 patients, respectively. The rate of Child-Pugh class A patients in the D group was significantly higher than that of the other groups (P<0.05). The average levels of ALT, TB and PT-INR in the D group were significantly lower than the levels in the other groups (P<0.05). The average Alb level in the D group was significantly higher than that in the other groups (P<0.05). In conclusion, we found that HCV-related HCC in the elderly occurred against a background of chronic liver disease with mild inflammation and fibrosis.

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Suppressive effect of oestradiol on chemical hepatocarcinogenesis in rats

Cited by 15 publications

References 8 publications

Mapping a Sex Hormone–Sensitive Gene Determining Female Resistance to Liver Carcinogenesis in a Congenic F344.BN-Hcs4 Rat

Mapping a Sex Hormone–Sensitive Gene Determining Female Resistance to Liver Carcinogenesis in a Congenic F344.BN-Hcs4 Rat

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

HCC develops even in the early stage of chronic liver disease in elderly patients with HCV infection

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