Fibroblast growth factor inhibits luteinizing hormone-stimulated androgen production by cultured rat testicular cells.
The effect of fibroblast growth factor (FGF) on LH-stimulated testosterone production was investigated using primary cultures of rat testicular cells. Testicular cells obtained from neonatal rats (8-9 days of age) were maintained in culture for 3 days and then challenged with LH with or without basic FGF. After 3 additional days of culture, the media were collected for steroid RIA. LH treatment of cultured cells stimulated testosterone production in a dose-dependent fashion whereas FGF alone did not affect androgen biosynthesis. In contrast, cotreatment with FGF caused a dose-dependent decrease of LH-stimulated testosterone production, with an IC50 value of 1.1 X 10(-9) M (as calculated from three separate experiments). The inhibitory effect of FGF was evident 24 h after the initiation of treatment and this effect was reversible 1 day after the cessation of FGF treatment. The inhibition of LH-induced testosterone production by FGF (maximal inhibition greater than 90%) was accompanied by a 12-fold increase in progesterone levels, suggesting that the inhibitory effect of FGF was distal to the step of progesterone formation. FGF also inhibited forskolin (10(-5) M)- and (Bu)2cAMP (5 X 10(-4) M)-stimulated testosterone production. Furthermore, FGF inhibited the conversion of exogenously added androgen precursors (progesterone and 17 alpha-hydroxyprogesterone) to testosterone in LH-stimulated cultures indicating that FGF might inhibit 17 alpha-hydroxylase activity. The concept of a direct testicular action of FGF was further supported by the demonstration of high affinity (Kd: 3.9 X 10(-10) M; n = 3 experiments) and low capacity (46,900 sites per cell) FGF receptors in cultured testis cells. The binding of [125I]FGF was inhibited by basic and acidic FGF but not by several other growth factors. In conclusion, we suggest that FGF binds to testicular cells and inhibits LH-stimulated testosterone production by inhibiting, at least partially, 17 alpha-hydroxylase enzyme activities. Because FGF has been purified from testis extracts, this growth factor may have intratesticular paracrine or autocrine functions.
Fauser
B C
BC
Department of Reproductive Medicine, School of Medicine, University of California, San Diego, La Jolla 92093.
Baird
A
A
Hsueh
A J
AJ
D019326:17-alpha-Hydroxyprogesterone; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D005346:Fibroblast Growth Factors / Q000378:metabolism / Q000494:pharmacology*; D006908:Hydroxyprogesterones / Q000378:metabolism; D007700:Kinetics; D007986:Luteinizing Hormone / Q000494:pharmacology*; D008297:Male; D011374:Progesterone / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013737:Testis / Q000187:drug effects / Q000378:metabolism*; D013739:Testosterone / Q000096:biosynthesis*
D006908:Hydroxyprogesterones; D011506:Proteins; D005576:Colforsin; D013739:Testosterone; D011374:Progesterone; D005346:Fibroblast Growth Factors; D003994:Bucladesine; D019326:17-alpha-Hydroxyprogesterone; D007986:Luteinizing Hormone