Neoplasms of the Reproductive Tract: The Role of Hormone Exposure

Abstract

Cancers of the reproductive system are a major source of morbidity and mortality among women worldwide. Because the uterus, ovaries, and cervix are hormonally responsive tissues, exposure to endogenous or exogenous sex steroids can profoundly affect the carcinogenic process. Animal models developed to date provide valuable but imperfect systems in which to study neoplasms of the reproductive tract. Nonhuman primate models share the unique primate-specific endometrial physiology of humans, but rarely develop neoplasms of the reproductive tract. Therefore a surrogate marker approach is required for the study of hormonally induced cancer risk in primates. Rodents provide practical models in which tumorigenesis can be assayed in a short time and, with appropriate interpretation, can be used for assessment of risk, prevention, and therapeutic strategies. In addition to the spontaneous strain-dependent incidence of female reproductive cancers, the classical chemical and hormonal carcinogenesis models, and the use of xenograft approaches, novel genetically modified animals provide unique insights into relevant molecular mechanisms. Caveats in the use of rodent models include anatomical differences from the human reproductive tract, the greater possibility of different metabolic responses to hormonal agents than humans, strain variations in tumor type and hormonal responsiveness, and unexpected tumor phenotypes in genetically modified animals. Reported nonmammalian models are limited primarily to the study of ovarian carcinogenesis. Recent progress in the understanding of cervical carcinogenesis is encouraging. Unmet needs in this area of research include models of early events in ovarian carcinogenesis and strongly predictive models of endometrial cancer risk. Nonhuman primates remain indispensable for the study of some aspects of reproductive pathophysiology, but the best understanding of carcinogenesis in the reproductive tract requires a broad approach using complementary human, nonhuman primate, and nonprimate studies.

Evolution of the human lifespan and diseases of aging: Roles of infection, inflammation, and nutrition

“…Adult baboons and monkeys had <3% prevalence at necropsy of >10,000 animals from 3 colonies that included older ages (55)(56)(57)(58)(59). Prosimian neoplasia is similar, 1%-3% of adults (60).…”

Prevention and treatment of cervical cancer in mice using estrogen receptor antagonists

“…Correspondingly, cervical cancers most commonly arise in the third to fifth decade (i.e., premenopausal period) of life in women (3). Furthermore, use of oral contraceptives or high parity has been shown to significantly increase the risk for cervical cancer in HPV-infected women (4,5).…”

“…Furthermore, use of oral contraceptives or high parity has been shown to significantly increase the risk for cervical cancer in HPV-infected women (4,5). These observations raise the possibility that steroidal hormones, such as estrogen, might affect cancers of the cervix, much like that of other hormonally responsive female organs (3,6). Estrogen replacement therapy alone, however, does not increase the risk for cervical cancer, and tamoxifen, a well-known estrogen receptor (ER) antagonist in breast, has no beneficial effect on cervical cancer (7,8).…”

Immunoexpression of Steroid Hormone Receptors and Proliferation Markers in Uterine Leiomyoma and Normal Myometrial Tissues from the Miniature Pig, Sus scrofa

“…Other animal models, including mice and guinea pigs, require genetic manipulation, tumor induction, or xenograft implantation as the incidence of spontaneous development is low as compared to women (Tsuiji et al , 2010, Romagnolo et al , 1996, Porter et al , 1995, Newbold et al , 2002). While nonhuman primates have the greatest similarity to the human female reproductive system and spontaneous occurrence of uterine leiomyomas has been reported in the Rhesus macaque (Simmons and Mattison, 2011), neoplasms of the reproductive tract are infrequent (Cline, 2004) and practical and ethical considerations have prevented extensive evaluation of this species. Overall, current animal models have inherent challenges to the extrapolation of data to humans.…”