NE, E Rajpert-De Meyts and KM Main. 2001. Testicular dysgenesis
syndrome: an increasingly common developmental disorder with environmental
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.
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.
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
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.
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.
Skakkebæk et al.
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.
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
is their evidence?
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
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."
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.
co-existence of several reproductive problems in one animal
should be seen in light of the knowledge about normal sex
differentiation and subsequent male fetal development. If
this sequence of events is disturbed at an early stage by
exposure to endocrine disruptors which affect differentiation
of the Sertoli cells and Leydig cells, germ cell proliferation
and testosterone production will be impaired. As these processes
are necessary for testicular descent and normal development
of the external genetalia, the end result will frequently
be a genital abnormality and/or cryptochidism in the newborn
animal, followed by fertility problems later in life. Even
though clinically detectable symptoms appear postnatally,
the underlying cause is irreversible testicular dysgenesis
during early fetal development."
also summarize several examples from wildlife studies showing that
contamination at levels experienced in the real world can cause
damage in free-living animals.
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.
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
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.
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:
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.
of lower sperm quality with other effects known to be pre-natal,
i.e., testicular cancer, cryptorchidism and hypospadias (see
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.
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.
cases of testicular cancer are caused by rare gene mutations.
When they occur, they are "often in combination with undescended
testis and hypospadias."
with testicular cancer are more likely than normal to have experienced
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.
non-cancerous testis of men with testicular cancer often has a
series of malformations related to TDS.
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.
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.
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.
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."
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.
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."