Silymarin is a selective estrogen receptor β (ERβ) agonist and has estrogenic effects in the metaphysis of the femur but no or antiestrogenic effects in the uterus of ovariectomized (ovx) rats

Silymarin is a widely used standardized mixture of flavonolignans and its major component Silybinin binds to cytosolic estrogen receptors. Here, we demonstrate that this binding is exclusive to the estrogen receptor β (ERβ). Treatment of ovariectomized (ovx) rats with silymarin or estradiol (E 2) may allow differentiation of biological effects mediated by the ERα or ERβ. E 2 inhibited serum LH, cholesterol, LDL and HDL concentrations in the blood and increased gene expression of IGF1, HbEGF and C3 in the uterus, while silymarin was totally ineffective or antagonistic in altering these parameters. Both, E 2 and silymarin inhibited expression of uterine ERβ gene. Hence, in the pituitary, liver (where the lipoproteins are synthesized) and uterus E 2 acts primarily via the ERα. Exclusive estrogenic effects of silymarin were observed in the metaphysis of the femur (MF), on osteoblast parameters (gene expression of IGF1, TGFβ1, osteoprotegerin, collagen-1α1, osteocalcin (OC)) and on the osteoclast activity marker tartrate resistant acid phosphatase (TRAP) gene expression of adult ovx rats. Our RT-PCR method detects ERβ gene expression in all organs including developing bones but not in the MF of adult ovx rats. We conclude therefore, that the effects of silymarin in this part of the bone cannot be exerted via the ERα because it does not bind to this receptor subtype. Despite the failure to detect ERβ mRNA in the MF of our animals the possibility exists that ERβ protein is present and may mediate the effects of silymarin. Another possibility may be that the effect of silymarin and therefore possibly also of E 2 in the MF may be mediated via other possibly not yet identified receptors or via an ERβ splice variant which is not detected by our PCR-method.