Sex Hormones as Endogenous Modifiers of Carcinogenesis

27 May

Sex Hormones as Endogenous Modifiers of Carcinogenesis

As noted in Table 8.3, removal of the primary sources of male and female hormones in mammals can have significant effects on chemical and radiation carcinogenesis. Thus, one must conclude that sex hormones can play a significant role as endogenous modifiers in carcinogenesis.  This should already be obvious from the statistical information presented in Chapter 1 and becomes even more so from the epidemiological  studies of human cancer (Chapter 11). In experimental animals, a highly significant effect of sex on chemical carcinogenesis is seen in the liver. With several aromatic amine carcinogens,  especially 2-AAF, hepatoma incidence is much higher in the male than in the female, as is the incidence of preneoplastic lesions after 2-AAF administra- tion (Tokumo et al., 1993). Interestingly, N-hydroxy-AAF is equally carcinogenic for both sexes in several strains of rats. In mice, there is a significant effect of the sex of the animal on sponta- neous mouse hepatoma  incidence (Table 8.4). The incidence of hepatomas  in female mice is slightly to markedly lower than the incidence of such lesions in males (Grasso and Hardy, 1975). Induced alterations in the endogenous sex hormone concentrations  also affect the incidence of mouse hepatomas. Breeding enhanced the incidence of hepatomas in males but inhibited the in- cidence in females (Burns and Schenken, 1943a,b). Castration of male C3H mice reduced the incidence of hepatomas in these animals by one-third but had little influence in CBA mice (An- dervont, 1950). The incidence of hepatic neoplasms was increased in female C3H mice treated with testosterone  (Agnew and Gardner, 1952). Thus, with few exceptions,  one may conclude that in the mouse, androgens promote hepatocarcinogenesis  while estrogenic hormones tend to inhibit this process (Poole and Drinkwater, 1996).

The mechanism for this differential effect of sex on hepatocarcinogenesis  is not entirely clear, but to some extent it is a function of the control of xenobiotic metabolism of endogenous and exogenous carcinogenic agents. Early studies by Lotlikar (1970) demonstrated that the en- zymic esterification of 2-N-hydroxy-AAF was significantly higher in the male than in the female rat, while earlier studies by this investigator  (Lotlikar  et al., 1964) demonstrated  that hypo- physectomy  decreased the urinary excretion of N-hydroxy-AAF.  Weisburger et al. (1964) had earlier reported a difference  in the excretion  of hydroxylated  forms of 2-AAF by males and females.  Male rats are also more sensitive  than females to the toxic actions of aflatoxin  B1 (Kamdem et al., 1982).

A more subtle mechanism  of hormonal modification  of carcinogenesis  may be seen in the effects of gonadectomy  and sex hormone administration  during the neonatal period. This “imprinting” of the expression of genes of xenobiotic and steroid metabolism by hormones and xenobiotics, as distinguished from genetic imprinting (Chapter 5), is a more general phenome- non, the molecular basis of which is unclear (Skett and Gustafsson, 1979). Such “imprinting” may result from the exposure of newborn rats to a number of drugs including phenobarbital (Haake and Safe, 1988), thus effecting a more or less permanent increase in specific xenobiotic enzymes that can alter the metabolism of carcinogens in later life (Faris and Campbell, 1981). In addition,  carcinogens  themselves  may imprint genes of xenobiotic  metabolism  when ad- ministered during the neonatal period (Herd and Greene, 1980; Soyka, 1980). However, with reference  to sex hormones,  testosterone  administered  in the neonatal  period causes a sub- sequent enhancement of specific cytochrome P450 forms (Chang and Bellward, 1996; Shimada et al., 1987) as well as enzymes of steroid metabolism (Chang and Bellward, 1996; cf. Skett and Gustafsson,  1979).  Administration  of diethylstilbesterol,  a potent  synthetic  estrogen, during the neonatal period alters the capacity of adult female rats to form and/or dispose of DNA adducts  of aflatoxin  B1  metabolites  after a single dose of the carcinogen  to the adult (Lamartiniere, 1990).

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