REGULATION OF EXTRAGONADAL INSULIN-LIKE GROWTH FACTOR-BINDING PROTEIN-3 BY TESTOSTERONE IN OOPHORECTOMIZED WOMEN

Insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) is the principal carrier protein of IGF-I in the circulation. IGF-I has been postulated to play a role in the genesis and maintenance of the polycystic ovary syndrome. Regardless of the exact mechanism of action of IGF-I on ovarian steroidogenesis, alterations in the level of IGFBP-3 may play a significant role in regulating the concentration of IGF-I in hyperandrogenism. We have postulated that androgens reduce the circulating IGFBP-3 concentration through a mechanism similar to its suppression of the hepatic production of sex hormone-binding globulin (SHBG), thereby increasing bioavailable IGF-I and amplifying its impact on ovarian steroidogenesis. To test this hypothesis, we studied seven oophorectomized women (aged 39-51 yr; body mass, 20.9-35.8 kg/m(2)) during 3 weeks of testosterone (T) propionate administration (20 mg, three times weekly). All subjects were receiving 0.625 or 1.25 mg conjugated estrogens/day. Blood was sampled before (week 0), during (weeks 1-3), and after (week 4) T administration. Serum was assayed for total T, GH, and SHBG, and plasma was assessed for IGF-I, insulin (INS), and IGFBP-3 IGFBP-3 was measured by both RIA and Western ligand blotting; (expressed as a percentage of the control value). Circulating T increased from 1.51 +/- 1.06 to 30.8 +/- 13.8 nmol/ L by week 2 (P < 0.001). During T administration, IGF-I increased(from 55 +/- 23 ng/mL at week 0 to 124 +/- 37 ng/mL at week 4;P < 0.05); INS did not change, with the exception of a higher fasting level 1 week after discontinuing therapy, and GH decreased (from 1.7 +/- 2.3 mu g/L at week 0 to 0.4 +/- 0.4 mu g/L at week 4; P < 0.03), as did the circulating SHBG concentration (397 +/- 205 to 273 +/- 93 nmol/L by week 2; P < 0.01). IGFBP-3 levels determined by Western ligand blot were higher during the second and third weeks of T administration (265 +/- 28% and 218 +/- 43% of Control values, respectively; P < 0.05) compared to that at week 0 (165 +/- 44% of control values). However, there was nb difference in the circulating concentration of IGFBP-3, determined by RIA, at weeks 0, 1, 3, and 4 (3.59 +/- 0.35, 4.00 +/- 0.79, 3.48 +/- 0.56, and 3.65 +/- 0.52 mu g/mL, respectively). Nonetheless, the plasma IGF-I concentration increased (from 55.0 +/- 23.4 mu g/mL at week 0 to 123.9 +/- 37.3 mu g/mL at week 4; P < 0.05), and the immunoreactive IGF-I to IGFBP-3 ratio increased linearly (from 16.1 +/- 5.7 at week 0 to 27.6 +/- 8.7 at week 4; P < 0.03). In conclusion, an increase in the circulating T concentration did not suppress circulating IGFBP-3 levels, as occurred with SHBG. Nonetheless, a linear increase in the IGF-I to IGFBP-3 ratio was noted, suggesting that free IGF-I may increase with androgen excess. The clinical significance of these findings in the maintenance of the polycystic ovary syndrome remains to be determined, because the T levels achieved in this study were well above those normally found in affected women. Finally, the impact of androgens on hepatic production/secretion appears to differ for SHBG vs. IGFBP-3.