Central to the cause of irreversible<unk>  are disruptions to early fetal testes development. This has genetic, environmental, and lifestyle components, however the rapid increase in the incidence of the disorders associated with<unk>  in the last decades indicates that it is under a powerful environmental influence. The fetal origins of<unk>  are reinforced by the high incidence of<unk>  disorders found occurring together in one individual. Associated with mutation of Insulin like Factor 3 (INSL3) Genetic Many genes have been implicated in the disorders of<unk> , with genome wide association studies (GWAS) regularly identifying new gene variants that play a role in abnormal testes development. Some of these are specific to certain disorders, and some are part of a 'risk factor network' that connect TGCC, hypospadias, cryptorchidism, poor semen quality. The majority of these genes are involved in fetal gonad development. Mutations in androgen receptor genes are highly implicated, as these are involved in penile development, testes descent, and testes development.<unk>  germ cell cancer (TGCC) shows a strong genetic disposition, with the most significant gene variants being those linked to gonad formation and germ cell function. Environmental Exposure of a male fetus to substances that disrupt hormone systems, particularly chemicals that inhibit the action of androgens (male sex hormones) during the development of the reproductive system, has been shown to cause many of the characteristic<unk>  disorders. These include environmental estrogens and anti-androgens found in food and water sources that have been contaminated with synthetic hormones and pesticides used in agriculture. In historical cases, medicines given to pregnant women, like diethylstilbestrol (DES), have caused many of the features of<unk>  in fetuses exposed to this chemical during gestation. The impact of environmental chemicals is well documented in animal models. If a substance affects Sertoli and Leydig cell differentiation (a common feature of<unk>  disorders) at an early developmental stage, germ cell growth and testosterone production will be impaired. These processes are essential for testes descent and genitalia development, meaning that genital abnormalities like cryptorchidism or hypospadias may be present from birth, and fertility problems and TGCC become apparent during adult life. Severity or number of disorders may therefore be dependent on the timing of the environmental exposure. Environmental factors can act directly, or via epigenetic mechanisms, and it is likely that a genetic susceptibility augmented by environmental factors is the primary cause of<unk> . Lifestyle Links between maternal smoking and<unk>  are tenuous, but there are stronger associations between maternal alcohol consumption and incidences of cryptorchidism in sons. Smoking does however affect the growth of a fetus, and low birth weight is shown to increase the likelihood of all the disorders encompassed by<unk> . Maternal obesity, resulting in gestational diabetes, has also been shown to be a risk factor for impaired testes development and<unk>  symptoms in sons.
Testicular dysgenesis syndrome
Cryptorchidism
XX male syndrome
XX gonadal dysgenesis
XY gonadal dysgenesis
Androgen insensitivity syndrome
Uhl anomaly
Wolf–Hirschhorn syndrome