Testosterone Formation and Metabolism During Male Sexual Differentiation in the Human Embryo

The formation by the gonads of 3H testosterone from 7α-3Hpregnenolone and 1,2-3H progesterone and the metabolism of 1,2-3Htestosterone by various tissues have been studied in 33 human fetuses that varied in age from phenotypically undifferentiated stages (1–3 cm crown-rump length) to sexually differentiated male and female embryos greater than 21 cm in length. In the first series of studies utilizing thinlayer and celite column chromatography for quantification of the metabolic products following incubation of the gonads with the C21 steroids, it was concluded that testosterone is the principal androgen formed by the fetal testis at the time of male sexual differentiation. The capacity for testosterone formation from these precursors was shown to rise from undetectable levels at 1–3 cm of development to maximal rates of about 150 pinoles/10 mg tissue/2 hr in the testes obtained from embryos of 7.1–9 cm crown-rump length, a sequence that correlates closely with the androgenmediated events in male sexual differentiation. No testosterone formation was demonstrated in the ovaries at any stage of development. To characterize the mechanisms involved in androgen-mediated development of the male urogenital tract, the rate of conversion of 1,2-3H testosterone to 3Hdihydrotestosterone was measured in a variety of tissues in these embryos. Dihydrotestosterone formation was most rapid in the tissues of the urogenital tract. In the urogenital sinus and urogenital tubercle the capacity for dihydrotestosterone formation was maximal prior to the onset of male differentiation, suggesting that dihydrotestosterone is probably the effective intracellular androgen that mediates male development in these tissues. In contrast, in the wolffian ducts the ability to form dihydrotestosterone could not be demonstrated until late in male differentiation, indicating that testosterone itself is the likely hormone that initiates the development of this anlage into the epididymis, vas deferens, and seminal vesicle. The implications of these findings for the elucidation of the pathogenesis of several disorders of male sexual differentiation have been discussed