To evaluate possible 17-ketosteroid reductase deficiency, we studied two sisters with primary amenorrhea, hirsutism, clitoral enlargement and a 46,XY karyotype, who lacked breast development. Plasma luteinizing hormone, follicle-stimulating hormone and urinary 17-ketosteroids were elevated in both subjects. Plasma Δ4-androstenedione was seven to nine times greater than normal, whereas plasma testosterone was low or in the low-normal male range. Spermatic venous plasma of Case 2 contained increased amounts of Δ4-androstenedione and estrone and subnormal amounts of testosterone and estradiol, findings consistent with testicular 17-ketosteroid reductase deficiency. In vitro incubation of testicular tissue of Case 2 confirmed a partial defect in testicular 17-ketosteroid reductase activity and documented increased 3β-hydroxysteroid dehydrogenase activity. Failure of breast development was probably due to lower estrogen levels than in previously reported cases. We conclude that testicular 17-ketosteroid reductase deficiency may cause male pseudohermaphroditism even in the absence of gynecomastia. (N Engl J Med 291:938–944, 1974), CONGENITAL deficiency of testicular enzymes essential for the synthesis of testosterone results in failure of development of normal male genitalia.1 2 3 4 A recently described testicular enzymatic deficiency causing male pseudohermaphroditism concerns 17-ketosteroid reductase (17-KSR), which converts Δ4-androstenedione (A) to testosterone (T) and estrone (E1) to estradiol (E2).5 Breast development has been present in all published cases.5 6 7 8 9 10 The two siblings with defective testicular reduction of A to T did not have breast development. These cases have been previously reported as examples of pseudovaginal perineoscrotal hypospadias.11 Case Histories Two sisters were seen at the ages of 18 (Case.
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