Circulating levels of GH, IGF-I, IGFBP-3 and sex steroids decrease with normal aging. IGFBP-3 increases after GH or sex steroid treatment. To date, there is little information on the effects of GH and/or sex steroid administration on other IGFBPs. In a double-blind, placebo-controlled, randomized study, we assessed the effects of 26 weeks of administration of GH, sex steroids (Estraderm+Provera = HT in women, or T enanthate in men), or GH+sex steroids on AM fasting levels of IGF-I, IGFBPs-1-5, insulin, glucose, and osteocalcin, as well as 2 hour urinary excretion of deoxypyridinolline (DPD) cross-links, in 53 women and 71 men aged 65-88 years (mean 72 y). At baseline, there were no significant group differences in IGF-I or IGFBP levels in either sex. In untreated women and men, respectively, there were significant direct relationships of IGF-I with IGFBP-3 (p< 0.001 and p< 0.0001) and of IGFBP-1 with IGFBP-2 (p=0.0001). In women, there were inverse relationships of IGFBP-1 with insulin (p< 0.0005) and glucose (p< 0.005) levels, and of IGFBP-4 with osteocalcin levels (p< 0.01). There were no significant relationships of IGFBP-4 or IGFBP-5 with urinary DPD cross-links in either sex. In women and men, administration of GH and GH+sex steroid, but not sex steroid alone, significantly increased IGF-I levels with higher IGF-I levels in men (p<0.001). In women, the IGF-I increment after GH was attenuated by co-administration of sex steroid (p<0.05). Hormone administration also increased IGFBP-3. IGFBP-1 levels were unaffected by GH and/or sex steroids in either sex, whereas GH administration decreased IGFBP-2 levels by 15% in men (p<0.05). Hormone administration did not change IGFBP-4 levels, whereas in men, IGFBP-5 levels increased by 20% after GH (p<0.05), and by 56% after GH+T (p=0.0003). These data demonstrate a sexually dimorphic response pattern of IGFBP's after GH administration, perhaps owing to sex differences in overall GH responsiveness. In addition, in women receiving GH+HRT vs GH alone, HRT appeared to attenuate the increase in IGF-I, and prevent the increase in IGFBP-3. Whether in vivo administration of GH and/or sex steroids alters local tissue production of IGFBP's, and whether the latter influence autocrine or paracrine actions of IGF-I, remain to be determined.