Testicular cancer and infertility

The potential links between the detrimental environmental effects on reproduction and the worldwide increase in testicular cancer evoke huge interest in clinicians, scientists, and the public.^1–3 The retrospective study by Jacobsen and colleagues in this issue (p 789) shows that men with abnormal semen analyses are at an increased risk of testicular cancer.⁴ These results provide more substantial evidence to support earlier studies reporting an increased incidence of testicular cancer in men who have few children for their age.⁵ The results show a higher risk in men with lower sperm counts, especially when combined with abnormal motility and abnormal sperm morphology, all of which suggest a more serious testicular defect.

The observation that the highest risk is found within the first two years after the semen analysis may be related to the early age at which the peak incidence of testicular cancer occurs.⁴ Most studies indicate that most testicular cancers occur before 40 years, a finding that strongly suggests that the cellular events leading to this cancer start at an early age, if not in fetal life.⁶ Such a view is supported by cellular features that are common to carcinoma in situ cells, which represent the precursors of the major testicular cancers, and gonocytes, the precursors of spermatogonia, the stem cells for spermatogenesis. Carcinoma in situ is more common in men with infertility, in accordance with the observed link between abnormal semen analysis and risk of testicular cancer.⁴,⁷ Furthermore, carcinoma in situ is also more frequent in undescended testes, a condition linked to an increased risk of testicular cancer and infertility.⁸

The specfic links between the pathological events that cause infertility, undescended testes, and testicular cancer remain unclear. Some concepts suggest an abnormality in Sertoli cells in the fetal or neonatal period. Sertoli cells (the supporting cells in the seminiferous tubules that control the intratubular environment) supply key metabolites to germ cells and transduce hormonal signals to germ cells, and an abnormality in their functioning may alter the fate of gonocytes.⁶ Instead of differentiating to form spermatogonia and thus initiating spermatogenesis, the gonocytes may remain in the testis and become subsequently transformed to develop into carcinoma in situ cells. These carcinoma in situ cells have a 50% chance at five years of becoming an invasive tumour. Since the Sertoli cells perform crucial functions that initiate and sustain spermatogenesis, an abnormality in their function may disrupt spermatogenesis.

Since these cells are also responsible for the production of Mullerian inhibiting substance, the absence of which has been linked to certain forms of testicular maldescent, it is possible that malfunction of the Sertoli cell may be a common link between these conditions.⁹ Some investigators propose that the cause of the abnormal function of Sertoli cells may result from their exposure to endocrine disruptors and high maternal oestrogens.³,¹⁰ Additionally, Tarone et al have reported an increased risk of testicular cancer in American serviceman who were in Vietnam, linking this observation to exposure to toxic agents.¹¹

For the clinician, the study in this issue strengthens the link between infertility and cancer of the testis, but it is important to note that the increased risk of 1.6 fold is small.⁴ It nevertheless adds to other risk factors, of which the most important is the link with undescended testes and infantile hernia; these result in, respectively, a fourfold and twofold increase in cancer of the testis, as noted in a large case-control study.¹² Interestingly, these authors noted that the increased risk of testicular cancer disappeared if orchidopexy was performed before 10 years of age. Testicular cancer is the most common form of cancer in men between men aged 15-44, and as its presentation is usually to the family doctor, it is important that risk factors are identified to heighten awareness.

Paper p 789