Testicular Cancer and Hormonally Active Agents∗

∗Two papers published after acceptance of the current manuscript have shed significant new light on the possible role of estrogen exposure in TC etiology. A meta-analysis of the evidence linking fetal exposures to pharmacological estrogens and subsequent development of TC concluded that such exposures roughly doubled the risk of TC (Martin et al., 2008). A second study demonstrated that estradiol impairs seminoma cell proliferation by acting through a nuclear receptor (ER beta) but stimulated proliferation by acting through a rapid acting cell surface receptor. This observation illustrates the complexity of estrogen action on germ cell proliferation and identifies a non-typical estrogen receptor as a possible target for exogenous estrogens to promote the development of TC.

Bouskine, A., M. Nebout, B. Mograbi, F. Brucher-Davis, C. Roger, and P. Fenichel. 2008. Estrogens Promote Human Testicular Germ Cell Cancer through a Membrane-Mediated Activation of Extracellular Regulated Kinase and Protein Kinase A. Endocrinology 149: 565–573.

Martin, O. V., T. Shialis, J. N. Lester, M. D. Scrimshaw, A. R. Boobis, and N. Voulvoulis. 2008. Testicular dysgenesis syndrome and the estrogen hypothesis: A quantitative Meta-analysis. Envir Health Perspect. 116:149–157.

Abstract

Testicular cancer (TC) is a rare form of cancer, accounting for 1% of all new cancer cases in Canadian males. TC is the most common malignancy among young men, aged 25–34 yr old. Over previous decades, the incidence of TC has increased in many Western countries. Countries with a sufficiently long period of cancer registration, such as Denmark, document this trend back to the first half of the 20th century. The etiology of TC remains poorly understood. Most of the established risk factors are likely related to in utero events, including some factors that are purported to be surrogate measures for exposure to endogenous estrogens. The correlation of TC with other testicular abnormalities and with pregnancy factors led to the proposal that these conditions are a constellation of sequelae of impairment of testicular development called testis dysgenesis syndrome. There is some limited evidence suggesting that exposure to pharmacological estrogens may contribute to some cases of TC. There is currently no compelling evidence that exposure to environmental estrogenic or other hormonally active substances is contributing to the rise in TC incidence observed in Western nations over the last several decades; however, this question has not been extensively studied. The (1) rarity of this condition in the population, (2) long lag time between the presumed sensitive period during fetal development and clinical appearance of the condition, and (3) lack of a good animal model to study the progression of the disease have greatly hindered the understanding of environmental influences on TC risk.

We thank Fan Mo for editorial assistance. D. Krewski is the NSERC/SSHRC/McLaughlin Chair in Population Health Risk Assessment at the University of Ottawa.

Notes

∗Two papers published after acceptance of the current manuscript have shed significant new light on the possible role of estrogen exposure in TC etiology. A meta-analysis of the evidence linking fetal exposures to pharmacological estrogens and subsequent development of TC concluded that such exposures roughly doubled the risk of TC (Martin et al., 2008). A second study demonstrated that estradiol impairs seminoma cell proliferation by acting through a nuclear receptor (ER beta) but stimulated proliferation by acting through a rapid acting cell surface receptor. This observation illustrates the complexity of estrogen action on germ cell proliferation and identifies a non-typical estrogen receptor as a possible target for exogenous estrogens to promote the development of TC.

Bouskine, A., M. Nebout, B. Mograbi, F. Brucher-Davis, C. Roger, and P. Fenichel. 2008. Estrogens Promote Human Testicular Germ Cell Cancer through a Membrane-Mediated Activation of Extracellular Regulated Kinase and Protein Kinase A. Endocrinology 149: 565–573.

Martin, O. V., T. Shialis, J. N. Lester, M. D. Scrimshaw, A. R. Boobis, and N. Voulvoulis. 2008. Testicular dysgenesis syndrome and the estrogen hypothesis: A quantitative Meta-analysis. Envir Health Perspect. 116:149–157.