Testicular Germ Cell Cancer and Its Fetal Origins

As evident from the discussion in the section on environmental and lifestyle effects, the importance (and mechanisms) of male fetal induction of testicular dysfunction remains speculative. This is partly because it is still a new area and partly because of the inherent difficulties in establishing cause and effect involving the human fetus, particularly when any outcome, such as infertility/low sperm counts, may not manifest for two or more decades. Nevertheless, there is a good and proven example of a major human testicular disorder that involves fetal induction and adult manifestation, and this is tes-ticular germ cell cancer (testis cancer) (115). It is now established as firmly as possible that these cancers arise from premalignant transformed fetal germ cells (primordial germ cells or gonocytes) that are termed carcinoma-in-situ (CIS) cells (107,115-117) (see Fig. 3). The latter express numerous proteins that are also expressed by fetal germ cells but not by spermatogonia and other germ cells in the adult testis (115-117). For unknown reasons, affected fetal germ cells fail to differentiate normally into spermatogonia and, thus, retain many stem cell features, and their subsequent development results in their unstable transformation. These cells remain quiescent in the testis until puberty, when their multiplication is stimulated (presumably) by the same growth factors as are normal germ cells during spermatogenesis. Eventually, a germ cell tumor results. This is usually in the age range 15-45 yr, with a peak incidence at 25-30 yr (118,119). In most Western countries, testis cancer is the most common cancer of young (white) men and, were it not for the tremendous success of treatment (90% success rate), it would be the biggest killer of young men after road traffic accidents (120,121).

There are two particularly intriguing aspects to testis cancer that make it highly relevant to this chapter. First, its incidence in young men has increased inexorably during the past 50-65 yr at least, and this increase is clearly linked to later year of birth (119,121). For example, a man born in Finland in 1965 has a more than 10-fold higher risk of developing testis cancer than a man born in Finland in 1905 (119). This increase owes nothing to better diagnosis or that we are living longer (it is a cancer of young men). In most Western countries, the incidence of testis cancer has doubled every 20-35 yr and a rapid increase like this can only have an environmental or lifestyle cause. However, it is equally clear that there is a genetic or ethnic component that predetermines testis cancer risk, because American blacks have a considerably lower incidence than do American whites (121,122). There are also other geographic (possibly ethnic) differences in testis cancer incidence, such as Oriental men having a lower incidence than Western Caucasian men (4), Finnish men having a fourfold lower incidence than Danish men (118,119). Most of the identified risk factors for testis cancer are prenatal factors (4,6,8,123), and many of these factors are shared with those for cryptorchidism, hypospadias, and low sperm counts/infertility (6,8,106,123), which may also be increasing in incidence (4,8,103,124-126). Observations such as this give rise to the concept of a testicular dysgenesis syndrome that may have several manifestations but a common underlying mechanism (6) (see Fig. 3). Indeed, this line of thinking can also encompass the ethnic differences in testis cancer incidence, reflecting factors such as genetic differences in hormone levels during pregnancy, or other factors that affect the intrauterine environment (8,123,127). Unfortunately, what is still lacking is a mechanistic appreciation of how ethnic and environmental/lifestyle factors affect the developing reproductive system of the fetus, other than knowing that effects on androgens and/or estrogens are probably involved somewhere in the chain of events

(5,8). If this was understood, then appropriate changes to lifestyle or diet could be recommended to minimize risk to the male offspring.

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