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Effects of the Selective Estrogen Receptor Modulator, Raloxifene, on the Somatotropic Axis and Insulin-Glucose Homeostasis

Department of Endocrinology, Academic Hospital Vrije Universiteit (A.M.O., N.P., G.A., C.P.-S., P.L.), 1007 MB Amsterdam, The Netherlands; and Prevention Sciences Group, University of California (T.D.), San Francisco, California 94105

Address all correspondence and requests for reprints to: Paul Lips, M.D., Department of Endocrinology, Academic Hospital, Vrije Universiteit, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. E-mail: p.lips{at}azvu.nl

Abstract

Raloxifene is the first selective estrogen receptor modulator registered for the prevention and treatment of postmenopausal osteoporosis. In addition to direct effects on bone cells, estrogen and raloxifene may act indirectly via changes in hormonal homeostasis. However, the menopause-related decrease in serum insulin-like growth factor I (IGF-I) and the increase in insulin or glucose are not always reversed by estrogen replacement. Especially orally administered estrogen was reported to decrease serum IGF-I levels. Understanding the effects of estrogens and raloxifene on the GH-IGF axis and insulin-glucose homeostasis are important because of their link to bone metabolism and cardiovascular health.

We investigated the effects of raloxifene on the GH-IGF-I axis and insulin-glucose homeostasis in a cross-sectional study in the third year of the Multiple Outcomes of Raloxifene Evaluation trial, a double blind, placebo-controlled, prospective study in postmenopausal women with osteoporosis (T-score of -2.5 or less or at least two moderate vertebral fractures). Patients with diabetes mellitus were excluded from this additional study. A fasting blood sample was obtained (0 h), and women received an sc injection of 0.05 mg recombinant human GH (Humatrope)/kg BW. The second blood sample was obtained 24 h later (24 h). GH, IGF-I, IGF-binding protein-3 (IGFBP-3), insulin, and glucose were measured. Group characteristics were tested by nonparametric ANOVA. The dose-response to raloxifene was tested by linear regression models, with age and body mass as covariates.

Seven women were taking placebo, 16 were taking raloxifene (60 mg/day), and 9 were taking raloxifene (120 mg/day). Patients from the 60 mg raloxifene group were the oldest (mean ± SD, 64.4 ± 4.2 vs. 69.3 ± 6.9 and 63.3 ± 5.9 yr for placebo, 60 mg/day raloxifene, and 120 mg/day raloxifene, respectively; P = 0.05). Compared with placebo users, patients taking raloxifene had higher body mass index (24.7 ± 1.7 vs. 25.0 ± 3.1 and 28.8 ± 5.8 kg/m²; P = 0.03). At 0 h, raloxifene use was associated with lower IGF-I/IGFBP-3 ratio (4.3 ± 0.7 vs. 2.9 ± 0.7 and 3.0 ± 0.7 nmol/mg; P = 0.001) and insulin/glucose ratio (13.7 ± 5.2 vs. 11.9 ± 5.9 and 9.5 ± 2.3 pmol/mmol; P = 0.04). Similarly, raloxifene use was associated with lower IGF-I/IGFBP-3 and insulin/glucose ratios at 24 h (P = 0.01 and 0.07). Glucose, GH, and IGFBP-3 levels were similar among the groups (0.12 < P < 0.67).

In conclusion, raloxifene use is associated with decreased serum IGF levels and insulin/glucose ratio before and 24 h after one rhGH injection in nondiabetic postmenopausal women with osteoporosis. Therefore, raloxifene may decrease liver sensitivity to GH. Other explanations are increased clearance or increased tissue sensitivity to IGF-I or insulin. The raloxifene-induced increases in bone mineral density do not appear to be mediated by reversing the age- and menopause-related decreases in IGF-I levels. The results of this small cross-sectional study need confirmation by longitudinal studies.

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