Long-term effects of the rhapontic rhubarb extract ERr 731® on estrogen-regulated targets in the uterus and on the bone in ovariectomized rats

The efficacy of the commercially available extract ERr 731® from Rheum rhaponticum L. regarding attenuation of menopausal complaints like hot flushes, depression, anxiety and vaginal dryness has been proven in a two-year clinical study. Further, no undesired side effects like uterotrophy or proliferation of the endometrium became apparent while testing ERr 731® in a 3-day uterotrophic assay. The present study aimed at further substantiating the safety of application of ERr 731® regarding endometrial hyperplasia and at the same time test for potential bone sparing effects in the preclinical ovariectomized (ovx) rat model. For this purpose we performed a 90d dietary feeding study in ovx rats. The impact of exposure on uterine proliferation was investigated by assessing the mRNA levels of proliferation marker genes (Mki67, Pcna) in comparison to the expression of the mRNAs of the estrogen receptors ESR1 and ESR2 and the estrogen response gene C3. To test for potential effects on the bone, we additionally performed densitometry analysis of the proximal tibia metaphysis using peripheral computed tomography and quantified bone homeostasis marker in the serum. With this study design, neither an uterotrophic response nor a modulation of mRNA levels of proliferation markers was detected after 90d of dietary exposure with the rhapontic extract. Furthermore, no effect of the two administered doses of ERr 731® on E2 deprivation induced bone loss became apparent. In conclusion, the observations from previous trials regarding the endometrial safety of ERr 731® application were substantiated, but no effect on the Bone Mineral Density could be observed.

Keywords: Rheum rhaponticum, ovariectomized rat, bone loss, endometrium, proliferation