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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

Davis, Susan R. MD, PhD1; Stuckey, Bronwyn G.A. MD2; Norman, Robert J. MD3; Papalia, Mary-Anne MD1; Drillich, Ann MD1; Bell, Robin J. MD, PhD1

doi: 10.1097/gme.0b013e318174f16e
Articles

Objective: Oral estrogen therapy suppresses insulin like growth factor I (IGF-I) levels, whereas conventional dose transdermal estradiol (E2) does not. However, it has been proposed that if sufficiently high serum E2 levels are achieved, nonoral E2 will also suppress serum IGF-I. The aim of the study was to investigate the effects of intranasal E2 with norethisterone (E2/NET) versus oral E2/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 E2/NET (175 μg/275 μg) as a spray and a placebo tablet (n = 41) or oral E2/NET acetate (1 mg/0.5 mg) plus placebo intranasal spray (n = 41) for 1 year. Fasting plasma concentrations of 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 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.

Oral estrogen therapy suppresses IGF-I levels whereas conventional dose transdermal estradiol does not. It has been proposed that if sufficiently high serum estradiol levels are achieved, non oral estradiol will also suppress serum IGF-I. In this study, intranasal estradiol at a dose that results in serum levels that exceed the proposed threshold for GH and IGF-I effects did not alter IGF-I levels. This suggests that the effect of exogenous estrogen on IGF-1 is a function of the method of administration rather than being dose related.

From the 1Women's Health Program, Department of Medicine, Monash Medical School, Alfred Hospital, Prahran, Victoria, Australia; 2Keogh Institute for Medical Research, Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, School of Medicine and Pharmacology, University of Western Australia, WA, Australia; and 3Adelaide Hormone and Menopause Centre, Research Centre for Reproductive Health, University of Adelaide, SA, Australia.

Received February 24, 2008; revised and accepted March 17, 2008.

Financial disclosure: None reported.

Address correspondence to: Susan Davis, MD, PhD, Women's Health Program, Department of Medicine, Central and Eastern Clinical School, Monash University, Alfred Hospital, Commercial Road, Prahran, VIC 3181, Australia. E-mail: susan.davis@med.monash.edu.au

©2008The North American Menopause Society