Revisiting the dual role of androgens and oestrogens in mammalian sex differentiation with a focus on genitalia.

Androgen signalling is the primary driver of male sexual differentiation in mammals, directing masculinization during a crucial fetal window. In male fetuses, high levels of fetal androgens, mainly from the testes, promote male reproductive tract development through androgen receptor activation, whereas low levels of androgens in female fetuses enable the development along the female pathway. This androgen-centric view of reproductive development has long dominated the field, casting oestrogens as passive bystanders. However, both historical and emerging evidence challenges this narrative, pointing to an active role of oestrogens in shaping reproductive development through complex, tissue-specific interactions with androgen pathways. Oestrogen receptors are expressed in developing reproductive tissues of both sexes, and disruptions in oestrogen signalling - shown in genetic and pharmacological models - can lead to reproductive abnormalities. Oestrogens might counteract androgen action at the tissue level and modulate androgen receptor expression, independently of effects on androgen production. Moreover, combined exposure to anti-androgens and oestrogenic compounds can amplify developmental disruptions, underscoring the importance of hormonal crosstalk. These findings question the adequacy of an androgen-only model, especially when assessing endocrine disruptors. Understanding the role of oestrogens is essential for interpreting normal development and chemical risks. Reproductive differentiation seems to depend on the integrated balance between androgen and oestrogen pathways, rather than on isolated signals.