Pathways of endocrine disruption during male sexual differentiation and masculinization

Best practice & research, Clinical endocrinology & metabolism, 2006


After testis formation, further development of a male phenotype (masculinization) is driven by three hormones from the foetal testis: anti-Müllerian hormone, insulin-like factor, and testosterone. These hormones divert the development of reproductive and other organs from female to male and also play a role in testis development. The hormone dependence of masculinization renders this process inherently susceptible to disruption by factors that interfere with hormone production, bioavailability, metabolism, or action. This susceptibility is illustrated by the high prevalence of congenital masculinization disorders (cryptorchidism, hypospadias) and disorders in young adult men (low sperm counts, testis cancer), which may also stem from maldevelopment (dysgenesis) of the foetal testis. Testicular dysgenesis occurring in humans, or which is induced in animal models by foetal exposure to certain phthalates, is associated with impaired hormone production by the foetal testis. There is currently no definitive evidence that exposure of humans to environmental chemicals can induce testicular dysgenesis and/or impair masculinization, though pathways via which this could potentially occur are established.

Concern about endocrine disruption of masculinisation has been fuelled by two pieces of information. The first is the evidence that mild disorders of the masculinisation process in humans are common and may be increasing in prevalence. Chief amongst these are the occurrence of cryptorchidism (testicular maldescent) and hypospadias (an abnormality in position of the urethral opening on the penis). However, it has also become increasingly apparent that male reproductive disorders which manifest in young adulthood (low sperm counts, testicular germ cell cancer) may also originate from disruption of the same early processes. The second factor driving concern about endocrine disruption of masculinisation is that this process, via which the basic female ‘set-up’ programme is rewritten to deliver a phenotypic male, is absolutely hormone-dependent , and is thus inherently susceptible to disruption by factors that can alter production or action of these hormones.

It is also not difficult to imagine that the different steps that comprise early testis development could go awry to a greater or lesser extent; the result of this would be termed dysgenesis. At its worst, widespread failure of normal seminiferous cord formation could occur, which would be bound to result in consequent failure of spermatogenesis, and therefore of fertility, in adulthood. This can occur in some patients due to certain chromosomal disorders (e.g. XY) in which a Y chromosome is present; such patients are frequently under-masculinised with ambiguous genitalia and are at high risk of developing testicular germ cell cancer.

It is becoming increasingly apparent that expression of AR, and probably of steroid receptors in general, is regulated primarily via alteration of the rates of receptor degradation rather than from altering the rate of receptor gene transcription and mRNA translation. This has been most clearly demonstrated for the AR, in which altered proteosomal degradation has been shown to occur in response to abnormally high exposure to potent oestrogens. This ability of over-exposure to oestrogens to dramatically reduce AR expression in reproductive target tissues in the male rat has been well described, and raises the possibility that environmental oestrogenic chemicals could induce similar effects and thus interfere with masculinisation. However, though there are isolated examples where such effects have been claimed, it appears that where the action of a potent (e.g. diethylstilboestrol) and a weak environmental oestrogen (e.g. bisphenol A) are compared directly, only the potent oestrogen is able to induce such an effect, and even then only at very high doses. Nevertheless, as this effect of oestrogen action is still poorly understood, it remains possible that some environmental chemicals might be able to target this particular pathway and thus interfere with androgen action during masculinisation.



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