We applied the ACTH-stimulation test developed in our laboratory for the detection of heterozygous carriers of the 21-hydroxylase deficiency gene to patients suffering from hirsutism (n=89), premature pubarche (n=75), early puberty (n=37), and precocious puberty (n=22), While, in the general population, this test is positive in less than 2%, we found in 33% of hirsute patients, in 41% of patients with premature pubarche, and in 33% of patients with early puberty a hormonal response similar to the one seen in heterozygous carriers for the 21\x=req-\ hydroxylase defect. In contrast, only 18% of patients with precocious puberty responded abnormally. Thus we speculate that, at least in some patients with hirsutism, premature pubarche, and early puberty, heterozygosity for the 21-hydroxylase defect plays a major role in the pathogenesis of these disorders.

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HLA (human leucocyte antigens) alleles and plasma 17-hydroxyprogesterone levels after ACTH stimulation were studied in 134 German families of patients with salt-wasting (SW), simple virilizing (SV), and nonclassical (NC) late-onset forms of CAH. HLA typing revealed a genetic difference between the two classical disease forms. SW-CAH was strongly associated with Bw47 and SV-CAH was closely linked to B5. The nearly complete connection of NC-CAH with B14 was confirmed. Bw47 and B14 were mostly components of the normally rare haplotypes A3, Bw47, DR7 and Aw33, B14, DR1, respectively. They did not occur in the families' disease-unaffected haplotypes. The HLA linkage data were consistent with those obtained from the ACTH stimulation test which showed a higher 17-hydroxyprogesterone increase in the group of genetically defined heterozygous relatives of SW patients than in the groups of heterozygous members of SV and NC families.

Androgens stimulate development and growth of the external male genitalia. Since hypospadias represents the most common congenital abnormality in the male newborn and the mechanism of action in this disorder is still unclear, androgen binding was assessed in cultured fibroblasts from biopsies from genital skin of 10 patients with idiopathic hypospadias. For comparison, binding was determined in corresponding samples from 8 males with normal penile development and from 9 patients with known androgen resistance syndromes (testicular feminization, Reifenstein syndrome, pseudovaginal perineoscrotal hypospadias). Finally, binding was measured in 10 samples of nongenital skin. Maximum specific binding (Bmax) in idiopathic hypospadias varied from 3.2 to 15.5 (median 6.6) fmol.mg protein-1. Bmax in samples of persons with normal genital development was between 12.2 and 17.9 fmol.mg protein-1 (median 13.2). Bmax in samples of patients with known androgen resistance syndromes was exactly in the range reported previously in the literature. It is evident that Bmax in samples of patients with idiopathic hypospadias differs significantly (P less than 0.01), (Mann Whitney U-test) from those with normal genital development. Thus it seems reasonable to conclude that in some patients with idiopathic hypospadias the genital defect is caused by receptor deficiency.