OBJECTIVE: Oestrogens can modulate the action or secretion of GH. Previous studies in postmenopausal women have shown a differential effect between transdermal 17beta-oestradiol and oral ethynyl-oestradiol on GH and IGF-1 concentrations. This secondary analysis, based on a large randomized trial, aimed to estimate the effect of the route of administration of 17beta-oestradiol in combined hormone replacement therapy with progesterone on IGF-1 and IGFBP-3 levels. DESIGN: IGF-1 and IGFBP-3 were evaluated in a randomized study of 196 healthy postmenopausal women who were randomly allocated to receive on a continuous basis either 1 mg of 17beta-oestradiol orally combined with a daily intake of 100 mg progesterone (group 1; n = 63), or 50 microg of 17beta-oestradiol transdermally combined with a daily intake of 100 mg progesterone (group 2; n = 68), or triple dummy placebo (group 3; n = 65) over a 6-month period. IGF1 and IGFBP-3 levels were available for 133 women. RESULTS: Oral oestrogen significantly decreased IGF-1 levels compared to placebo (P = 0.04) and transdermal oestrogen (P = 0.004), whereas transdermal oestrogen had no effect on IGF-1 levels compared to placebo (P = 0.56). As regards IGFBP-3, no significant difference was detected between the three groups. CONCLUSIONS: Our data indicate that the route of oestrogen administration can influence IGF-1 levels. IGF-1 concentrations decreased significantly with oral oestrogen, whereas no significant change was observed with transdermal oestrogen at 6 months. The clinical relevance of these differential effects remains to be determined, particularly with regard to the risk for cardiovascular diseases.