Androgen induction of steroid 5 alpha-reductase may be mediated via insulin-like growth factor-I.
The action of added insulin-like growth factor-I (IGF-I) and dihydrotestosterone (DHT) on steroid 5 alpha-reductase (5 alpha R) activity was studied using primary cultures of rat or human scrotal skin fibroblasts. Agents were added to cultured cells (2 x 10(5) cells) for 2 days, and enzyme activity was measured by the percent conversion of [3H] testosterone to DHT over a 4-h period in the absence of fetal calf serum or other growth factors. DHT, but not testosterone, at 10(-7) M significantly increased 5 alpha R activity (rat, 1.5 +/- 0.3% to 3.0 +/- 0.4%; human, 7.6 +/- 1.7% to 11.4 +/- 2.9%; P < 0.01). IGF-I (10(-9)-6.4 x 10(-9) M), but not IGF-II (10(-9)-10(-8) M) or insulin (10(-9)-10(-7) M), increased enzyme activity in a dose-related fashion [i.e. 1.5 +/- 0.5 to 10 +/- 2 in rat and 6.0 +/- 1.1 to 9.8 +/- 1.6% (P < 0.01) in human cells]. No change in cell numbers was observed in any experiment. Since the effect of IGF-I was about 100 times that of androgen, we studied the possibility that androgen induction of the enzyme activity could be via IGF-I production. Addition of a monoclonal antibody against IGF-I significantly reduced the effect of DHT, and simultaneous addition of a specific IGF-I receptor antibody blocked the expected induction of 5 alpha R activity (control, 4.9 +/- 0.5; DHT, 8.0 +/- 1.9; DHT plus IGF-I receptor antibody, 3.7 +/- 0.4%). No effect on 3 alpha-reduction of [3H]DHT to 3 alpha-androstanediol was detected in separate experiments. These studies indicate that IGF-I may be an important regulator of skin 5 alpha R activity and, thus, may influence DHT formation. The previously known androgen induction of this peripheral steroidogenic enzyme may be via paracrine/autocrine production of an IGF-I-type growth factor.
Horton
R
R
Department of Medicine, University of Southern California School of Medicine, Los Angeles 90033.
Pasupuletti
V
V
Antonipillai
I
I
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000096:biosynthesis*; D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal; D002478:Cells, Cultured; D013196:Dihydrotestosterone / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D005347:Fibroblasts / Q000201:enzymology; D007328:Insulin / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000276:immunology / Q000494:pharmacology / Q000502:physiology*; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012611:Scrotum
D000728:Androgens; D000911:Antibodies, Monoclonal; D007328:Insulin; D013196:Dihydrotestosterone; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase