Endocrine Abstracts

Androgens are essential regulators of human foetal testis development and play a critical role in male sexual differentiation. Following sex-determination, the bipotential gonads develops into testes under the control of the SRY gene, and subsequently the paracrine and endocrine activity of the foetal testis becomes central to further male development. In the human foetal testis, Leydig cells begin producing testosterone from approximately 7–8 weeks of gestation, initiating androgen-dependent processes that are essential both within the testis itself and in peripheral target tissues. Testosterone supports the maintenance of the Wolffian ducts and the differentiation into internal male reproductive structures, but the foetal Leydig cells also secrets INSL3 which plays a critical role directing testicular descent. The secreted testosterone is converted to the more potent dihydrotestosterone (DHT) in target tissues, which is essential for the masculinisation of the external genitalia. Accordingly, disruption of androgen synthesis or action due to either genetic or non-genetic factors can result in incomplete virilisation of the male foetus. Within the foetal testis itself, androgens exert important paracrine effects that support the development of testicular organisation, cell lineage differentiation, and function. These aspects were recently examined in an ex vivo culture model of human fetal testis in which pharmaceutically induced reduction in androgen exposure was found to affect both Leydig and Sertoli cell function as well as germ cell numbers. Although neither Sertoli cells nor germ cells express the androgen receptor at this developmental time-point, both cell populations exhibited alterations in response to reduced androgen exposure. This suggests that androgen signalling was mediated indirectly through other testicular cell types, most likely fetal Leydig cells–to exert effects on the overall foetal testis development and function. In conclusion, sufficient androgen exposure and action, particularly during a critical developmental window in early fetal life is essential to ensure correct differentiation and function of all cell types within the developing testis. Thus, the androgens produced by the human foetal testis are indispensable, both locally for testicular development and systemically to ensure male sexual differentiation.