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

• Published in: The journal of clinical endocrinology and metabolism Vol. 86; no. 10; pp. 4741 - 4746
• Main Authors: Elmlinger, Martin W., Mayer, Iris, Schnabel, Doris, Schuett, Burkhardt S., Diesing, Dagmar, Romalo, Gabriela, Wollmann, Hartmut A., Weidemann, Wolfgang, Spindler, Klaus-Dieter, Ranke, Michael B., Schweikert, Hans-Udo
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01-10-2001
• Subjects: Androgen-Insensitivity Syndrome - metabolism; Biological and medical sciences; Cells, Cultured; Fibroblasts - metabolism; Genitalia, Male - metabolism; Gynecology. Andrology. Obstetrics; Humans; Insulin-Like Growth Factor Binding Protein 2 - biosynthesis; Insulin-Like Growth Factor Binding Protein 2 - genetics; Insulin-Like Growth Factor II - biosynthesis; Insulin-Like Growth Factor II - genetics; Male; Male and female genital diseases. Gonadal dysgenesis. Hermaphroditism. Sex hormones resistance; Medical sciences; Receptors, Androgen - chemistry; RNA, Messenger - analysis; Endocrinopathy; Human; Androgen; Pathogenesis; Male; Sexual differentiation disorder; Gene expression; Congenital disease; Insulin like growth factor 2; Male pseudohermaphroditism; Insulin like growth factor binding protein; Target tissue resistance; Malformation; Adult; Skin; Sex steroid hormone; Male genital diseases; Fibroblast
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jcem.86.10.7883

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 currently 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
compared the expression of IGFs and IGF-binding proteins in cultured
genital skin fibroblasts from nine patients with the syndrome of
complete androgen insensitivity with that in genital skin fibroblasts
from 10 normally virilized males. Mutations in the AR gene and/or
abnormalities of the AR protein in the immunoblot were detected in all
complete androgen insensitivity genital skin 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. Most strikingly, complete androgen
insensitivity genital skin fibroblast strains produced significantly
lower IGF-II (P < 0.001; 42.2 ± 9.7
vs. 106.9 ± 11.8 ng/mg protein) and IGF-II mRNA
(P < 0.01, by RT-PCR) than control genital skin
fibroblast strains. The production of IGF-binding protein-2 was also
decreased (P < 0.03) in complete androgen
insensitivity genital skin fibroblasts, whereas that of IGF-binding
protein-3 did not differ. Furthermore, high levels of IGF-binding
protein-5 mRNA were detected in all genital skin fibroblast strains,
whereby the 28-kDa band in the ligand blot, probably representing
IGF-binding protein-5, was more abundant in complete androgen
insensitivity genital skin fibroblasts. Exposure of the genital skin
fibroblasts to T (5 × 10−8 m) had
only weak effects on the expression of IGFs 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 involved in the mediation of androgen action
and growth of genital tissues.