Decreased expression of IGF-II and its binding protein, IGF-binding protein-2, in genital skin fibroblasts of patients with complete androgen insensitivity syndrome compared with normally virilized males

The action of androgen by way of the AR is required for the development of male gonads and external genitalia. The interplay between androgens and the somatotropic axis, in particular the IGFs in sexual development, is curren tly under thorough investigation. The IGF system is thought to mediate the androgen action in androgen-responsive cells. To investigate the interaction of androgens with the IGF system, we compare d the expression of IGFs and IGF-binding proteins in cultured genital skin fibroblasts from nine patients with the syndrome of complete androgen insen sitivity with that in genital skin fibroblasts from 10 normally virilized m ales. Mutations in the AR gene and/or abnormalities of the AR protein in th e immunoblot were detected in all complete androgen insensitivity genital s kin fibroblast strains. They caused a complete failure of DHT binding. RIA and RT-PCR demonstrated that the genital skin fibroblast strains expressed IGF-II, IGF-binding protein-2, and IGF-binding protein-3, but no IGF-I. Mos t strikingly, complete androgen insensitivity genital skin fibroblast strai ns produced significantly lower IGF-II (P < 0.001; 42.2 +/- 9.7 vs. 106.9 /- 11.8 ng/mg protein) and IGF-II m-RNA (P < 0.01, by RT-PCR) than control genital skin fibroblast strains. The production of IGF-binding protein-2 wa s also decreased (P < 0.03) in complete androgen insensitivity genital skin fibroblasts, whereas that of IGF-binding protein-3 did not differ. Further more, high levels of IGF-binding protein-5 mRNA were detected in all genita l skin fibroblast strains, whereby the 28-kDa band in the ligand blot, prob ably representing IGF-binding protein-5, was more abundant in complete andr ogen insensitivity genital skin fibroblasts. Exposure of the genital skin f ibroblasts to T (5 x 10(-8) M) had only weak effects on the expression of I GFs and IGF-binding proteins. In conclusion, although the mechanism underlying these differences requires further study, it is conceivable that in addition to the endocrine actions of IGF-I, IGF-II and IGF-binding protein-2, as local growth factors, are i nvolved in the mediation of androgen action and growth of genital tissues.