Further Development 6.7: Steroids and Secondary Sex Determination

Testosterone is one of the two primary masculinizing factors, but there is evidence that it is not the active masculinizing hormone in certain tissues. Although testosterone promotes formation of the male structures that develop from the Wolffian duct, testosterone does not directly masculinize the urethra, prostate, penis, or scrotum. Instead, this is controlled by a derivative of testosterone, 5α-dihydrotestosterone (DHT) (Figure 1). Testosterone is converted to DHT in the urogenital sinus and swellings (Siiteri and Wilson 1974), but not in the Wolffian duct. DHT appears to be a more potent hormone than testosterone and is most active prenatally and in early childhood.¹ The importance of this was demonstrated in a study of a syndrome in a small community in the Dominican Republic (Imperato-McGinley et al., 1974). Individuals with this syndrome lack the enzyme that converts testosterone to DHT (Andersson et al. 1991; Thigpen et al. 1992). Chromosomally XY children with this syndrome have functional testes, Wolffian duct development, and Müllerian duct degeneration. The testes, however, do not descend before birth, and the children appear to be girls and are raised as such. At puberty, however, the testes start producing high levels of testosterone, overriding the lack of DHT, causing the penis to enlarge, the scrotum to descend, and the person to be revealed as a young man. The external genitalia, therefore, are under the control of dihydrotestosterone, whereas Wolffian duct differentiation is controlled by testosterone. The steroid hormone estrogen is needed for fertility in both males and females. In females, estrogen induces the differentiation of the Müllerian duct into the uterus, oviducts, cervix, and upper vagina. In female mice whose genes for estrogen receptors are knocked out, the germ cells die in the adult, and the granulosa cells that had enveloped them start developing into Sertoli-like cells (Couse et al. 1999). Male mice with knockouts of estrogen receptor genes produce few sperm, and the concentration of sperm that occurs in the rete testis is disrupted, leaving the mouse sterile (Hess et al. 1997). Although blood concentrations of estrogen are in general higher in females than in males, the concentration of estrogen in the rete testis is higher than in female blood.

Literature Cited

Andersson, S., D. M. Berman, E. P. Jenkins and D. W. Russell. 1991. Deletion of steroid 5a-reductase 2 gene in male pseudohermaphroditism. Nature 354: 159–161.
PubMed Link

Couse, J. F., S. C. Hewitt, D. O. Bunch, M. Sar, V. R. Walker, B. J. Davis and K. S. Korach. 1999. Postnatal sex reversal of the ovaries in mice lacking estrogen receptors alpha and beta. Science 286: 2328–2331.
PubMed Link

Hess, R. A., D. Bunick, K.-H. Lee, J. Bahr, J. A. Taylor, K. S. Korach and D. B. Lubahn. 1997. A role for oestrogens in the male reproductive system. Nature 390: 509–512.
PubMed Link

Imperato-McGinley, J., L. Guerrero, T. Gautier and R. E. Peterson. 1974. Steroid 5a-reductase deficiency in man: An inherited form of male pseudohermaphroditism. Science 186: 1213–1215.
PubMed Link

Siiteri, P. K. and J. D. Wilson. 1974. Testosterone formation and metabolism during male sexual differentiation in the human embryo. J. Clin. Endocrinol. Metabol. 38: 113–125.
PubMed Link

Thigpen, A. E., D. L. Davis, T. Gautier, J. Imperato-McGinley and D. W. Russell. 1992. The molecular basis of steroid 5a-reductase deficiency in a large Dominican kindred. N. Engl. J. Med. 327: 1216–1219.
PubMed Link

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¹. There’s a reason why the label on some hair restoring drugs warns pregnant women not to handle them. Finasteride, an active ingredient in these products, blocks the metabolism of testosterone into DHT and thus could interfere with the gonadal development of a male fetus.