Testicular Dysgenesis Syndrome

 What we know
 Incidence
 Environmental risk factors
 CHEM Trust materials on male reproductive health

What we know

Testicular dysgenesis syndrome (TDS) comprise a group of disorders in newborn boys (undescended testes or cryptorchidism and hypospadias, where the urethral opening is wrongly located on the penis) and young men (low sperm count, testicular germ cell cancer), with a common foetal origin, associated with incorrect cell development in the testis [1].

Although these disorders used to be analysed separately, existing evidence supports the theory that these male reproductive disorders are all symptoms of a disruption in embryonic development. Evidence includes the observation that testicular cancer, cryptorchidism, hypospadias and poor spermatogenesis share several risk factors such as low birth weight, and are all risk factors for each other - men with undescended testis and/or hypospadias are significantly over-represented among patients with testicular cancer. Also, patients with rare genetic abnormalities that cause testicular dysgenesis (like 45X0/46XY and androgen insensitivity) are associated with high risk of testicular cancer, often combined with cryptorchidism and hypospadias [2].

Incidence

Large geographic variations in incidence are further indication of a common underlying developmental disorder. Denmark has a high prevalence of rates of cryptorchidism and hypospadias and poor semen quality. Finland on the other hand, has low prevalence of each of these disorders, and overall shows good male reproductive health [3].

Figure 1: The ENVI.REPROD.HEALTH Project, EU Fifth Framework Programme Click here

Despite problems of underreporting, differences in registration systems and inclusion criteria European populations show overall upward trends in hypospadias, cryptorchidism [4], testicular cancer and declining sperm counts [5], [6]. A Danish study reports that 5 - 6% of school boys have undescended testes and almost 1% have penile abnormalities when they are born. Furthermore over 40% of young adult men have subnormal sperm counts [7].

Figure 2: Age standardised rates for incidence of testicular cancer [8]

Figure 3: Prevalence of hypospadias at birth (rate per 10,000 births) in England, Wales and Hungary [9]

Figure 4: Interactive regression model for mean sperm density by year and geographic region, after controlling for proven fertility, abstinence time, age, specimen collection method, method of counting sperm, whether the study was included by Carlsen et al., and interaction of region and study year. [10]

Male reproductive development requires the interaction of many hormones, in particular androgens, testosterone and dihydrotestosterone (DHT). The programming mechanisms that regulate the interaction of these hormones are delicately balanced.

Environmental risk factors

Given both the short time span over which it has occurred and the fact that today we are exposed to a complex mixture of chemicals, a reasonable hypothesis is that the increase in TDS and geographical clustering is due to adverse environmental influences and lifestyle factors acting during early foetal development.

Although more research is needed, it is suggested that male reproductive development is disrupted in utero via increased oestrogen (hormone responsible for female sexual development and reproduction) exposure or exposure to chemicals that act as anti-androgens (androgens are chemicals responsible for the development and maintenance of the male sexual characteristics). The chemical hormone disruptors, also known as endocrine disruptors, implicated include: plasticisers such as phthalates, used in many every-day products to make plastics more pliable, dicarboximide fungicides such as Vinclozolin, organochlorine-based insecticides, polybrominated diphenyl ethers (PBDEs), conazole fungicides, and urea-based herbicides.

Since World War II many complex chemicals have been introduced to the environment, some of which are reproductive toxicants. Whilst efforts are underway to monitor the effects of toxicants on reproductive processes and understand the mechanisms involved in the development of TDS, that exposure to environmental chemicals can impair male reproductive health is extremely plausible. In light of this, the focus of attempts to address the increasing disease burden should be preventive action aimed at reducing exposure to endocrine disrupting chemicals.