Effects of the route of estrogen administration on insulinlike growth factor-I, IGF binding protein-3, and insulin resistance in healthy postmenopausal women: results from a randomized, controlled study

Objective: Oral estrogen therapy Suppresses insulin like growth factor I (IGF-I) levels, whereas conventional dose transdermal estradiol (E-2) does not. However, it has been proposed that if sufficiently high serum E-2 levels are achieved, nonoral E-2 will also suppress serum IGF-I. The aim of the study was to investigate the effects of intranasal E-2 with norethisterone (E-2/NET) versus oral E-2/NET acetate on IGF-I, IGF binding protein 3, and insulin resistance in postmenopausal women.Design: This was a randomized, multicenter, double-blind, double-dummy trial. Postmenopausal women were randomized to receive either daily intranasal E-2/NET (175 mu g/275 mu g) as a spray and a placebo tablet (n = 41) or oral E-2/NET acetate (1 mg/0.5 mg) plus placebo intranasal spray (n = 41) for 1 year. Fasting plasma concentrations of g IGF-I, IGF binding protein 3, glucose and insulin, glucose and insulin at 120 minutes post-glucose challenge, and the homeostasis model assessment for insulin resistance were assessed at baseline and after 52 weeks of treatment.Results: The two groups were well matched for all clinical and biochemical parameters at baseline. There were e no significant between-group differences for fasting and 120-minute glucose, insulin, homeostasis model assessment for insulin resistance, and IGF binding protein 3. The mean IGF-I level at week 52 was significantly lower for women treated with oral versus intranasal therapy (116 +/- 21 [SD] versus 134 +/- 33 [SD], P = 0.005) and the mean difference in change over 52 weeks in IGF-I was significantly different between groups (-19, 95% CI: -37 to -1, P = 0.04).Conclusions: In healthy postmenopausal women, intranasal E2 at a dose that results in serum levels that exceed the proposed threshold for growth hormone and IGF-I effects, does not alter IGF-I levels. This suggests that the effect of exogenous estrogen on IGF-I. is a function of the method of administration rather than being dose related.