METABOLIC FEATURES OF POLYCYSTIC-OVARY-SYNDROME ARE FOUND IN ADOLESCENT GIRLS WITH HYPERANDROGENISM

Recently, we reported that hyperandrogenism in adolescent girls is acc ompanied by augmented LH pulsatility and elevated LH/FSH ratio with in creased ovarian volume. Together with higher concentrations of 17-hydr oxyprogesterone, androstenedione, testosterone, and estrone that are o varian in origin, these neuroendocrine features are identical to those seen in adult women with polycystic ovary syndrome. In the present st udy, we report the metabolic characteristics of these hyperandrogenic adolescent girls. The GR insulin-like growth factor I(IGF-I)-binding p rotein (BP)-3 axis, insulin sensitivity, and insulin-IGFBP-1/insulin s ex hormone binding globulin axes were evaluated in 13 adolescent girls (ages 11-18 yr) with mild to moderate signs of hyperandrogenism (HA) and 28 age-matched normal girls. Insulin sensitivity was assessed by a frequent-sample iv glucose tolerance test (ivGTT, 0.3 g/kg). Twenty-f our hour blood samples were obtained at 10-min intervals and were used to determine GH pulsatility (20-min samples), IGFBP-3 levels (0800-09 00 h), and fluctuations of insulin, IGFBP-1, and IGF-I (hourly samples ) during feeding and fasting phases of the day. In addition, GH respon ses to GHRH stimulation (1 mu g/kg) were assessed. Pasting insulin con centrations, but not plasma glucose levels, were significantly elevate d in the KA group compared with those in the normal group (256 +/- 35 vs. 103 +/- 24 pmol/L, P = 0.0008), as were insulin responses to ivGTT and meals (P < 0.01) and 24-h mean insulin concentrations (P < 0.01). Thus, hyperinsulinemia with normal fasting glucose levels in HA girls may reflect insulin resistance, as suggested by the increased ratio o f insulin and glucose (P < 0.001). All measures of insulin were correw ith body mass index (BMI); however, insulin remained significantly hig her in the HA group after correcting for BMI, suggesting that decrease d insulin sensitivity was related to other factors in addition to BMI. Twenty-four hour IGFBP-1 concentrations showed a diurnal pattern with an inverse relationship to insulin, and 24-h mean concentrations were lower in the HA group (0.35 +/- 0.13 vs. 0.76 +/- 0.09 mu g/L, P = 0. 02). Reduced sex hormone binding globulin levels were also inversely r elated to insulin levels (P = 0.0007). In contrast, GH pulsatile chara cteristics and IGF-I/IGFBP-3 levels, as well as GH responses to GHRH, were similar between the groups. The activity of the GH-IGF-I axis in HA girls exhibited age- and BMI-dependent declines identical to those seen in,normal adolescent girls. Ovarian volume was larger in the HA g roup (P < 0.0001) and correlated independently with both 24-h mean con centrations of LH (P = 0.0002) and fasting insulin (P = 0.002). Basal serum concentrations of 17-hydroxyprogesterone, androstenedione, testo sterone, and estrone were positively correlated with LH levels; howeve r, an independent influence of insulin on steroid levels was unmasked during suppression of LH by the GnRH antagonist Nal-Glu. In conclusion , intrinsic abnormalities of the GH-IGF-IGFBP-3 axis were not found in adolscent girls with hyperandrogenism. The salient metabolic feature identified is hyperinsulinemia, which in concert with elevated LH leve ls and reduced IGFBP-1 and sex hormone binding globulin may contribute to the development of manifestations of polycystic ovary syndrome, es pecially increased ovarian volume, and ovarian hyperandrogenism. These observations reaffirm the peripubertal onset of this syndrome.