Estrogen and androgen production rates in two brothers with Reifenstein syndrome

Defects of the androgen receptor in 46,XY individuals cause aberrant virilization that varies from a female phenotype to men with minor defects. More severely affected individuals also develop gynecomastia associated with enhanced estradiol secretion by the testis. However, the degree of breast development does not correlate with the rate of estrogen production, leading us to propose that feminization is a function of the degree of androgen resistance as well as the rate of estrogen formation. To test this hypothesis we measured estrogen and androgen formation in two brothers with perineoscrotal hypospadias and severe gynecomastia (the Reifenstein phenotype) due to a mutation that impairs androgen receptor function. Rates of estradiol production (60 and 70 micrograms/day) were elevated, but were not as high as in previously studied men with a similar phenotype. We conclude that the variable degree of feminization in this disorder cannot be explained by androgen resistance alone.