Characterization of the pharmacologic profile of a standardized soy extract in the ovariectomized rat model of menopause: effects on bone, uterus, and lipid profile.
OBJECTIVE
This study was aimed to assess the effect of a standardized soy extract (SSE, Soyselect) in the ovariectomized rat model of menopause.


METHODS
Ovariectomized rats were treated for 6 weeks with the soy extract (50 or 100 mg/kg/day - PO), vehicle (distilled water), or 17beta-estradiol (0.5 mg/kg/day - PO). Tissue-specific estrogen agonist effects were examined using the endpoints bone mineral density, biochemical parameters of bone turnover, modulation of cytokines involved in the bone remodeling, uterine weight, uterine histology, uterine hormone receptor status, and serum lipid level.


RESULTS
The SSE produced a bone-sparing effect associated with a slowing down in the increased bone turnover observed after ovariectomy (as indicated by measurements of serum osteocalcin levels and excretion ratio of deoxypyridinoline); changes in serum interleukin-6 levels observed after SSE suggested that this bone-sparing effect could be partly attributed to the modulation of osteoclastogenesis induced by interleukin-6. Remarkably, organ weight data and histopathologic analysis did not show any stimulatory activity of the SSE on the uterus. Immunohistochemical analysis showed a significant down-regulation of estrogen receptor-alpha (ERalpha) in uterine epithelium after 17beta-estradiol treatment, but not after treatment with the SSE; no significant differences among groups were observed in ER-alpha uterine stromal levels. After treatment with 17beta-estradiol, estrogen receptor-beta (ER-beta) expression was not modulated in the stroma or epithelium, whereas the SSE induced an up-regulation of ER-beta stromal expression. Collectively, these results suggest that the lack of stimulatory activity on the uterine epithelium using soy treatment could be due to a negligible stimulatory activity on estrogen receptor-alpha and/or to the enhanced expression observed in stromal ER-beta, the latter being considered as a negative modulator of ERalpha-mediated uterine proliferation. 17beta-estradiol, but not the SSE, down-regulated uterine epithelial progesterone receptor (PR), compared with ovariectomized rats. In the stromal compartment, progesterone receptor expression was fully up-regulated by 17beta-estradiol treatment and, to a lesser extent, by SSE treatment. The minor increase in lipid levels induced by ovariectomy was not affected by SSE administration. Finally, the lack of stimulatory activity on uterus was also confirmed in an immature female rat model.


CONCLUSIONS
The results of this study demonstrated that the tested extract has an interesting profile of tissue-specific response, in that it is efficacious in preventing experimental osteoporosis without causing stimulation in uterus at doses that are effective in bone.
Gallo
Daniela
D
Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Rome, Italy.
Zannoni
Gian Franco
GF
Apollonio
Patrizia
P
Martinelli
Enrica
E
Ferlini
Cristiano
C
Passetti
Gianluigi
G
Riva
Antonella
A
Morazzoni
Paolo
P
Bombardelli
Ezio
E
Scambia
Giovanni
G
D000596:Amino Acids / Q000652:urine; D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight; D015519:Bone Density; D016723:Bone Remodeling / Q000187:drug effects*; D015536:Down-Regulation; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D004958:Estradiol / Q000097:blood / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism; D005260:Female; D019833:Genistein / Q000097:blood; D006965:Hyperplasia / Q000139:chemically induced; D015850:Interleukin-6 / Q000097:blood; D007529:Isoflavones / Q000097:blood; D008055:Lipids / Q000097:blood*; D008593:Menopause; D023421:Models, Animal; D009929:Organ Size; D015675:Osteocalcin / Q000097:blood; D010052:Ovariectomy; D010936:Plant Extracts / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011980:Receptors, Progesterone / Q000378:metabolism; D013025:Glycine max; D017154:Stromal Cells / Q000378:metabolism; D015854:Up-Regulation; D014599:Uterus / Q000033:anatomy & histology / Q000166:cytology / Q000378:metabolism*
D000596:Amino Acids; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D015850:Interleukin-6; D007529:Isoflavones; D008055:Lipids; D010936:Plant Extracts; D011980:Receptors, Progesterone; D015675:Osteocalcin; D004958:Estradiol; C004742:daidzein; C036020:deoxypyridinoline; D019833:Genistein