Skakkebæk, NE, E Rajpert-De Meyts and KM Main. 2001. Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Human Reproduction 16:972-978.

In this paper Skakkebæk et al. summarize emerging evidence that a collection of adverse conditions in male reproductive health have their basis in a common origin, specific errors during the development of fetal testes.

They propose that this collection of disorders should be recognized as a syndrome, testicular dysgenesis syndrome (TDS), and that it is likely to be caused by environmental factors in many cases, and by rare genetic disorders in others. Their proposal is based on well-established understanding of the way in which the male reproductive tract develops, particularly the way that variation in fetal hormonal levels can lead to disease and dysfunction.

The diagram below identifies the two sources of TDS, environmental factors and genetic defects, and then shows their consequences. One pathway of impact, via disruption in Sertoli Cell function, leads to reduced semen quality and testicular cancer. The other, through impacts on Leydig Cell function, causes hypospadias and cryptorchidism. The common origin, TDS, thus leads to a cluster of related health effects.

Skakkebæk et al. also propose that the presence of the symptoms varies with the severity of expression of the syndrome. Some people will express stronger cases than others. The most severe cases will involve three or four symptoms. In contrast, people with a less severe expression may have only one or two symptoms.

By Skakkebæk et al.'s model, less severe forms of TDS are more common, as indicated by the height of the left-most portion of the diagram, impaired spermatogenesis. More severe cases (toward right) are less common.   from Skakkebæk et al.

By this model, "TDS may be more common than immediately apparent because mild forms may present only with slight impairment of spermatogenesis." Danish data suggest that this mild form may be experienced by as much as one-fifth of Danish young men, based on evidence of low sperm counts there.

Skakkebæk et al. further suggest that the failure to recognize the common origins of poor sperm quality, undescended testes, hypospadias and testicular cancer has hindered research into causation. They recommend that "future epidemiological studies on trends in reproductive health should not focus on one symptom only, but be more comprehensive and take all aspects of TDS into account. Otherwise, important biological information may be lost."

What is their evidence?

First they briefly summarize "a wealth of data showing that male animals exposed in utero or perinatally to exogenous oestrogens (diethylstilbestrol, ethinyl oestradiol, bisphenol A) and anti-androgens (flutamide, vinclozolin, DDE, DDT) develop hypospadias, undescended testes, low sperm counts, or in the worst case, intersex conditions, teratomas and Leydig cell tumors."

They conclude that "all male reproductive problems in humans currently of concern in relation to environmental hazards can be experimentally produced in animals by pre-and perinatal exposure to endocrine disruptors—with the exception of germ cell cancer, for which, unfortunately, there is no suitable animal model."

They draw special attention to the fact that in animal experiments, these impacts will occur as a syndrome. Some animals have several at once while other animals appear normal.

They also summarize several examples from wildlife studies showing that contamination at levels experienced in the real world can cause damage in free-living animals.

Skakkebæk et al. then turn to the human experience. The evidence from basic, clinical and epidemiological studies "suggests that a large fraction of human male reproductive disorders is of antenatal origin," i.e., it began in the womb.

Why focus on events in the womb? Hypospadias and cryptorchidism are both present at birth; by definition they must stem from prenatal errors. The evidence on testicular cancer stems from Skakkebæk's own work, confirmed subsequently by others. He has shown that testicular cancer arises from cells that failed to develop normally while in the womb, cells he terms "carcinoma in-situ (CIS) cells." Testicular cancer, however, is not usually manifest clinically until at least 2 decades after birth, even though the developmental errors underlying most cases occurred in the womb.

Lower sperm quality is clearly influenced by a range of post-natal factors (age, smoking, pesticide exposure (DBCP), etc. The evidence that lower sperm quality can also be of pre-natal origin is based on three lines of reasoning:

• knowledge of the basic mechanisms of development of the male reproductive tract, for example, that there is a signficant relationship between the number of Sertoli cells and sperm density (more Sertoli cells means more sperm production), and that the number of Sertoli cells is determined by developmental processes during fetal life and before puberty.

• co-occurrence of lower sperm quality with other effects known to be pre-natal, i.e., testicular cancer, cryptorchidism and hypospadias (see immediately below).

• and epidemiological evidence that sperm quality is related to birth cohort. This is a standard indicator in epidemiological studies to mark effects that are likely to be due to in utero or perinatal events.

Skakkebæk et al. then examine patterns of co-occurrence in people of the four health effects they attribute to testicular dysgenesis syndrome: lowered sperm quality, undescended testis, hypospadias and testicular cancer. All four conditions tend to co-occur in people.

• Some cases of testicular cancer are caused by rare gene mutations. When they occur, they are "often in combination with undescended testis and hypospadias."
• Men with testicular cancer are more likely than normal to have experienced cryptorchidism.
• Men with cryptorchidism are more likely than normal men to come to infertility clinics; the undescended testis is often manifests problems related to misdirected development, including impaired (or arrested) sperm production.
• The non-cancerous testis of men with testicular cancer often has a series of malformations related to TDS.
• Men with testicular cancer of one testis have extremely low sperm counts, much lower than what would be expected on the basis of the loss of one functional testis.
• Research on sperm count of men who later developed testicular cancer confirms the presence of abnormal semen characterstics, including low sperm count, prior to the development of testicular cancer.
• Men who later develop testicular cancer are likely to have had fewer children than normal men, an indication of reduced fertility, and also to have sired fewer male children.

Why do they propose environmental factors as plausible causative agents? Skakkebæk et al. acknowledge that some cases of TDS are caused by genetic factors. But "in a significant number, perhaps the majority of newborns with malformations of genitalia, no chromosomal or other genetic defect can be demonstrated with our current knowledge." Further, the patterns of TDS showing geographical and temporal synchrony in the four syndrome elements, point to environmental factors. "In Finland, for example, the rates of testis cancer, undescended testis and hypospadias are much lower than among Danish men, who, in return, also have poorer semen quality. In addition, the rates of all these conditions are rising synchronously in both countries at a speed that strongly suggests that environmental factors are operating."

Of possible environmental factors, Skakkebæk et al. draw special attention to endocrine disruptors. In their opinion, while far from proven as the cause of TDS, "the endocrine disruptor hypothesis is relevant and plausible. Experience with DES, epidemiological work demonstrating patterns of genital malformations in children of workers exposed occupationally to pesticides, etc, are all consistent.

They conclude cautiously that "as the rise in the incidence of the various symptoms of TDS occurred rapidly over few generations, the aetiological impact of adverse environmental factors such as hormone disrupters, probably acting upon a susceptible genetic background, must be considered."