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

• Published in: The journal of clinical endocrinology and metabolism Vol. 86; no. 6; pp. 2763 - 2768
• Main Authors: Oleksik, Anna M., Duong, Tu, Pliester, Nicolette, Asma, Greetje, Popp-Snijders, Corrie, Lips, Paul
• Format: Journal Article
• Language: English
• Published: Endocrine Society 01-06-2001
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jcem.86.6.7549

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.