Hormonal Relationships in the Development of Human Cancer

25 May

Although hints and reports of a role for hormones and the causation of human cancer had ap- peared over the past several centuries, the first practical application of hormones in oncology was their use in the therapy of specific human neoplasms. The first practical application to the human of what little knowledge  existed at the time was the demonstration  by Huggins  and Hodges of the partial androgen dependence of many human prostatic cancers, as evidenced by the beneficial  effects of orchiectomy  or synthetic estrogens in many patients even with meta- static disease (Huggins and Hodges, 1941). Since then, significant evidence has developed to indicate a role for hormones in the development of several common human neoplasms. Miller (1978) pointed out such a relationship with breast, ovarian, endometrial, and prostate cancer in the human. More recently Henderson and colleagues (Henderson  et al., 1988) have presented reasonable evidence to argue for a major role of estrogens in cancers of the breast and genital tissues in both males and females. However, as Kodama and Kodama (1987) have pointed out along with others, a variety of additional  factors such as diet and other lifestyle components (Chapter  11) are involved  in the hormonal  interactions  with tissues that lead ultimately  to neoplasia.

To date there is little evidence for the carcinogenicity of polypeptide hormones in the hu- man, such as with the animal systems indicated above. The best evidence is for a role of thy- rotropin  in the genesis of human thyroid cancer, as referred  to above. In Williams’  review (1989), several epidemiological  studies indicated  that risk factors such as iodide deficiency, “dyshormonogenesis,”  and ionizing radiation were all associated with elevated thyrotropin lev- els in the serum of these individuals. Furthermore, patients with neoplasms of the pituitary that secrete high levels of growth hormone (Chapter 18) do have an increased risk of several types of malignant neoplasms (Barzilay et al., 1991). Thus, based on animal experimentation  together with these few epidemiological  studies, the data are suggestive of a carcinogenic effect of en- dogenous polypeptide pituitary hormones in the human analogous to experimental investigations in the animal.

That estrogens are carcinogenic in the human, either by direct or indirect mechanisms, was first exemplified by the report of the development of primary vaginal adenocarcinoma in young women whose mothers had taken diethylstilbestrol  (DES) during the first trimester of the rele- vant pregnancy (Herbst and Scully, 1970). A registry for such exposed women was developed, and in 1987 Melnick and associates (1987) reviewed 519 cases of clear-cell adenocarcinoma of the vagina and cervix in which the majority of the patients’ mothers had received DES or a re- lated hormone during pregnancy. The risk that such a neoplasm will develop in an exposed fe- male from birth through age 34 was found to be approximately 1 in 1000. On the other hand, the incidence of a nonneoplastic condition resulting from the retention of embryonic glands in the vagina and cervix, termed vaginal adenosis, was much higher, approaching 70% of females ex- posed to DES in utero (Johnson et al., 1979). As further support for the causative relationship of DES and this vaginal pathology, Newbold and McLachlan  (1982) reported that mice exposed prenatally or neonatally to DES developed both vaginal adenosis and adenocarcinoma.

For more than three decades, preparations of synthetic estrogens and progestogens, singly or combined, have been used as oral contraceptives by women in the United States (Huggins and Zucker, 1987). After the first decade of their widespread use, reports (Edmondson et al., 1976; Goldfarb, 1976) of a significant  increase in the incidence of liver adenomas  in women using such oral contraceptive preparations appeared. The increased risk of such lesions directly paral-leled the duration of use; after 8 years, there was a 500-fold increase in the risk of the develop- ment of hepatocellular  adenomas  in women using oral contraceptives  continuously  for this period (cf. Huggins and Zucker, 1987). The use of sequential oral contraceptives, in which estro- gen was given for 2 weeks followed by an estrogen-progestogen  combination  for 1 week, re- sulted in the occurrence of endometrial carcinoma in young women on this regimen (cf. Huggins and Zucker, 1987). Following the first reports of such occurrences (Silverberg and Makowski,

1975; Lyon, 1975), manufacturers  voluntarily removed such preparations from the market. As further documentation  of the carcinogenicity  of estrogens in the human, the administration  of synthetic or natural estrogens as hormone replacement therapy to postmenopausal  women has revealed a strong association between estrogen use and cancer risk. The risk is in proportion to dose and duration of use, with a three- to sixfold increase in risk after 3 to 10 years of use and a more than tenfold increment in risk after more than 10 years of using unopposed estrogen (Bar- rett-Connor, 1992). Strikingly, when exogenous estrogens given to postmenopausal  women are supplemented  with progestogens,  the risk of endometrial  cancer is dramatically  reduced (cf. Voigt et al., 1991). Thus, these findings with the use of exogenous estrogens further support the concepts of Henderson,  Miller, and others of the importance  of endogenous  hormones,  espe- cially estrogens, in the development of human cancers of a variety of tissues, most of which are recognized as end organs for estrogen effects.

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