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Vol. 287, Issue 1, 1-7, October 1998
Department of Endocrine Research, Lilly Corporate Center,
Indianapolis, Indiana
Body weight, uteri, serum cholesterol and bones were shown previously
in vivo to be sensitive to circulating levels of
estrogen, as well as to synthetic, nonsteroidal ligands termed
selective estrogen receptor modulators (SERM). In this study, we
examined the in vivo effects of a new potent SERM on
these tissues in 6-month-old, ovariectomized rats that were orally
dosed with 0.0001-10 mg/kg/day LY353381.HCl for 5 weeks. LY353381.HCl
prevented the ovariectomy-induced increase in body weight and serum
cholesterol levels of treated rats and lowered them to below sham
levels in a dose dependent manner, with maximum efficacy similar to
estrogen or raloxifene. However, LY353381.HCl was consistently more
potent than raloxifene, with a half maximal efficacious dose of 0.001 mg/kg for the reduction of body weight and cholesterol. In the uterus,
LY353381.HCl had marginal effects on uterine weight compared to
ovariectomized controls (OVX) like raloxifene, but unlike estrogen.
Histological examination of uterine epithelial cell height showed
little to no stimulatory effect of LY353381.HCl on the endometrium.
Quantitative computed tomographic analyses (pQCT) of tibiae showed that
LY353381.HCl prevented loss of bone due to ovariectomy with an
ED50 of about 0.01 mg/kg with maximal efficacy observed at
0.1-1 mg/kg/day. Maximally attainable bone mineral density and content
with LY353381.HCl were not significantly different from Sham or
ovariectomized rats treated with estrogen or raloxifene. Interestingly,
assessment of bone quality by biomechanical analyses showed that
LY353381.HCl preserved the strength of the femora neck and midshaft,
while improving the Young's modulus of cortical bone to beyond
estrogen, raloxifene or sham levels. In uteri of immature rats treated
with estrogen, LY353381.HCl antagonized the estrogen-induced elevation in uterine weight down to vehicle-dosed control levels with
ED50 of 0.03 mg/kg/day. Therefore, LY353381.HCl was 30-100
times more potent than raloxifene in preventing ovariectomy effects on
body weight, serum cholesterol and bone, while maintaining estrogen antagonist effects on the uterus. These animal data suggest that LY353381.HCl may have advantages over estrogen or raloxifene in the
prevention of bone loss and treatment of other tissues in postmenopausal women.
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