Male Infertility and Testicular Cancer – Points of Common Causality


Recent research has supported the existence of this increased risk, although the exact impact infertility or subfertility has on a man’s risk of developing testicular cancer is still disputed. A study by Jacobson reported the increased risk of testicular cancer in men with fertility problems to be 1.6 times that of men with normal semen parameters.7 A more recent study by Raman estimated the incidence of testicular cancer in infertile men to be 20 times greater than that of men with proven fertility (i.e. biological children).8


Perhaps one reason for the


discrepancies in these values is the multiple mechanisms that could potentially link male infertility and testicular cancer. Multiple genetic causes, as well as environmental variables, have been implicated to play a role as causal links between these two disease states.


Genetic Causes


Both male infertility and testicular cancer have been associated with the SRY gene, DNA repair genes and tumour suppressor gene mutations.9


Mutations in the SRY gene have been linked to gonadal tumour formation and infertility. Alterations of the SRY gene are most commonly associated with complete gonadal dysgenesis. Patients with these alterations can present with phenotypes ranging from streak gonads such as those seen in Turner syndrome to genital ambiguity. One meta-analysis noted gonadal tumour formation in 52.5% of patients with SRY abnormalities.10


Supraphysiological levels of reactive oxygen species (ROS) in the semen lead to oxidative damage to the sperm, which may manifest as DNA breakage, cross-linkage and mutations.11


shown that infertile men have high ROS levels in the seminal fluid.11


Recent studies have In


addition to causing DNA damage, ROS also results in the production of highly mutagenic compounds that can further increase an individual’s susceptibility to tumour formation.11


Chronic oxidative


damage is indicative of a deficiency in DNA repair mechanisms. In addition, mutations in these repair genes can result in deletions or expansions of small repeat DNA sequences, leading to unstable components that have been noted in many forms of cancer.12 Furthermore, these mutations and expansions of DNA repeat sequences can manifest as male infertility.12


Cases of male infertility and cancer formation have also been attributed to deficiencies in tumour suppressor genes, particularly p53. The gene plays a crucial role in tumour prevention and stress response pathways. It also helps to co-ordinate a variety of cellular responses from cell cycle arrest and apoptosis to the maintenance of genomic stability. This gene also has an important role in spermatogenesis – specifically during the prophase of meiosis within primary spermatocytes. Mutations result in chromosomal and genomic instability, increasing the chance that p53-null cells will become malignant and gain additional mutations.13


This genomic


instability would also compromise the sperm’s ability to fertilise an egg. It has also been reported that p53 has a role in the upregulation of certain antioxidant genes.14


leave the cell without an important defence against ROS. Therefore, at high ROS levels, such as those seen in infertile patients, the cell would be susceptible to an even greater amount of oxidative stress and subsequent DNA damage.


Environmental Causes


Researchers are currently focusing on endocrine-disrupting chemicals or xenoestrogens as a possible mediating factor linking


EUROPEAN UROLOGICAL REVIEW A knockout of this gene would thus


Intact and competent Sertoli cells are required for optimal spermatogenesis and spermiogenesis. Therefore, when these cells function improperly, hypospermatogenesis and infertility can occur.16 Additionally, the malfunctioning of Sertoli cells leads to the arrest of many gonocytes at an early stage of maturation. These arrested gonocytes are thought to be the forerunners to CIS (see Figure 1). Fifty per cent or more of those diagnosed with CIS will develop invasive testicular cancer within five years.17


Impaired testosterone and INSL-3 secretion


Hypospadias Cryptorchidism


Diminished capacity to nurture germ cells


Infertility


Testicular cancer


In this pathway, the key event is the impairment of testes development during foetal life.


testicular cancer and male infertility. These are antiandrogenic agents that mimic oestrogens.


Phthalates, gums and paints are antiandrogenic chemicals that are ubiquitous in human life. They have been used as plasticisers in polyvinyl chloride (PVC) products and are constituents of many infant toys, storage containers and medical devices.15


Figure 1: Proposed Mechanism Leading to Testicular Dysgenesis


Impaired foetal testes development


Decreased functioning of Leydig cells


Decreased functioning of Sertoli cells


While experts


recommend that daily exposure be limited to 2mg, with nearly 18 billion pounds of phthalates being produced per year, many individuals have occupational or medical exposures greatly in excess of these guidelines.15


These agents are believed to lead to an increase in oestrogen levels in the blood. This inhibits the hypothalamopitutary gonadal axis, resulting in decreased production of follicle-stimulating hormone (FSH) and, subsequently, a fixing of the Sertoli cell number or prevention of the production of additional Sertoli cells.


In most mammals, Sertoli cell replication occurs only during foetal and post-natal life. The Sertoli cell number thus becomes fixed at a particular stage of development. However, in humans the Sertoli cell number increases significantly between late foetal and pre-pubertal life and also increases further during puberty. Hence, the window for adverse effect on Sertoli cells in humans is longer than that known for other mammalian species. Thus, after exposure to environmental hormones, xenoestrogens or environmental endocrine disruptors, these chemicals accumulate in the body, and their effects are biomagnified over a period of time.


Additionally, as a 57


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