. Effects of GH and/or sex steroids on circulating IGF-I and IGFBPs in healthy, aged women and men. Am J Physiol Endocrinol Metab 290: E1006 -E1013, 2006. First published January 3, 2006 doi:10.1152/ajpendo.00166.2005.-Circulating GH, IGF-I, IGFBP-3, and sex steroid concentrations decrease with age. GH or sex steroid treatment increases IGFBP-3, but little is known regarding the effects of these hormones on other IGFBPs. We assessed the effects of 26 wk of administration of GH, sex steroids, or GH ϩ sex steroids on AM levels of IGF-I, IGFBPs 1-5, insulin, glucose, and osteocalcin and 2-h urinary excretion of deoxypyridinolline (DPD) cross-links in 53 women and 71 men aged 65-88 yr. Before treatment, in women and men, IGF-I was directly related to IGFBP-3 (P Ͻ 0.001 and P Ͻ 0.0001) and IGFBP-1 to IGFBP-2 (P ϭ 0.0001). In women, IGFBP-1 was inversely related to insulin (P Ͻ 0.0005) and glucose (P Ͻ 0.005) and IGFBP-4 to osteocalcin (P Ͻ 0.01). IGFBP-4 and IGFBP-5 were not significantly related to DPD cross-links. GH and/or sex steroid increased IGF-I levels in both sexes, with higher concentrations in men (P Ͻ 0.001). In women, the IGF-I increment after GH was attenuated by hormone replacement therapy (HRT) coadministration (P Ͻ 0.05). Hormone administration also increased IGFBP-3. IGFBP-1 was unaffected by GH ϩ sex steroids, whereas GH decreased IGFBP-2 by 15% in men (P Ͻ 0.05). Hormone administration did not change IGFBP-4, whereas in men IGFBP-5 increased by 20% after GH (P Ͻ 0.05) and 56% after GH ϩ testosterone (P ϭ 0.0003). These data demonstrate sexually dimorphic IGFBP responses to GH. Additonally, HRT attenuated or prevented GH-mediated increases in IGF-I and IGFBP-3. Whether GH and/or sex steroid administration alters local tissue production of IGFBPs and whether the latter influence autocrine or paracrine actions of IGF-I remain to be determined. growth hormone; insulin-like growth factor-binding protein INSULIN-LIKE GROWTH FACTOR-BINDING PROTEINS (IGFBPs) are members of a structurally and genetically related superfamily of proteins that bind to insulin-like growth factors (IGFs) with high, but variable, affinities (34). In addition to their principal roles as modulators of endocrine, paracrine, and autocrine actions of IGFs, IGFBPs exert growth hormone (GH)-independent effects on various tissues in vivo and in vitro (38, 59). The detailed mechanisms of IGFBP synthesis and their metabolic activities remain incompletely understood. However, it has been reported (6, 64, 65) that circulating levels of IGFBP-1 are regulated by insulin and IGF-I. IGFBP-2 is also related to insulin levels (13), whereas increases in IGFBP-3 are closely correlated with those in IGF-I in response to GH in children (47) and adults (39) with GH deficiency (GHD). IGFBP-4 and -5 inhibit and stimulate, respectively, IGF-mediated effects on bone (53). How these important modulatory proteins are affected by aging and age-related changes in endocrine balance and the extent to which hormone replacement reverses such changes is incomplet...