Estrogenicity of the medicinal botanicals red clover, milk thistle and saw palmetto Free

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In recent years, use of complementary and alternative medicine has increased by both healthy and cancer patients. Our previous work showed that many commonly used botanicals demonstrate estrogenic activity in vitro and in vivo. In this study, we examined three botanical extracts that have been reported to inhibit growth of human prostate carcinoma in vitro and in vivo. These extracts are: red clover (Trifolium pretense, RC), used for menopausal symptoms, hormone replacement, cancer prevention, and for digestive and respiratory diseases; milk thistle (Silybum marianum, MT), used as a liver tonic during chemotherapy and for liver disorders and injury; and saw palmetto (Serenoa repens or Sabal serrulata, SP): used for benign prostatic hyperplasia and urinary symptoms. We tested extracts of RC, MT and SP for estrogenicity in vitro using two competitive estrogen receptor (ER) binding assays, with female rat liver as source of ERα and rat prostate for ERβ. Extracts were also tested in the presence and absence of a physiological level of estradiol (E2, 1nM) in ER-positive breast cancer cell lines (MCF-7, predominantly ERα; T47D, predominantly ERβ) and ER-negative (BT-20), and in vivo using ovariectomized (OVX) female rats. In both receptor assays, dose-dependent inhibition of E2 binding was noted with RC and SP. MT competed with E2 at the lowest doses but enhanced binding at highest doses in both assays. In cell proliferation assays, RC caused growth in MCF-7 cells above E2 control levels, whereas in T47D cells, RC had a strong proliferative effect alone and a dramatic additive effect in the presence of E2. In MCF-7, SP was modestly proliferative at the weakest doses yet below E2-stimulated levels, and showed an additive effect with E2. In contrast, in T47D, SP produced a biphasic response, and when combined with E2, a strong additive effect. MT had a proliferative effect in MCF-7 equivalent to E2 stimulation, with an additive effect when combined with E2. In T47D, MT produced modest proliferation, and in the presence of E2, an additive effect beyond E2 stimulation. When fed to OVX female rats at a dose equivalent to 30% of the recommended human dose for 30 days, RC and MT did not increase uterine weight, and SP significantly decreased uterine weight. Serum LH levels were not reduced significantly by RC or MT, but reduced somewhat by SP. Serum E2 levels were not altered but for a slight increase with SP. Hepatic estrogen 2-hydroxylase activity was significantly reduced only by MT. In conclusion, these botanicals demonstrate some degree of estrogenicity. They interact with both ERα and ERβ, and in the presence of a physiological E2 level, may amplify ER-mediated cellular events. Both cell lines demonstrate proliferation in the presence of these extracts, with T47D showing a greater response. While these botanicals may have clinical applications, they should be avoided or used cautiously by patients with hormone-responsive diseases.