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While all three coactivators [ARA.sub.70], steroid receptor coactivator 1, and RAC3/ACTR can enhance androgen receptor (AR) transcriptional activity at 1 nM dihydrotestosterone, we here demonstrate that only [ARA.sub.70] can induce AR transcriptional activity >30-fold in the presence of 10 nM 17[Beta]-estradiol (E2), but not diethylstilbestrol. The significance of this newly described E2-induced AR transcriptional activity in DU145 human prostate cancer cells was further strengthened by finding patients with Reifenstein partial-androgen-insensitive syndrome that fail in the E2-AR-[ARA.sub.70] pathway. Together, our data suggest, for the first time, testosterone/dihydrotestosterone may not be the only ligands for the AR. E2 represents another important natural ligand for AR that may play an essential role for the AR function and the development of the male reproductive system.

Luteinizing hormone-releasing hormone antagonist SB-75 suppresses the development of OV-1063 human epithelial ovarian cancer xenografts in nude female athymic mice. SB-75 decreases the insulin-like growth factor I receptor and epidermal growth factor receptor levels in the tumor cell membranes. SB-75 is suitable for hormonal therapy of malignant cancer and functions through the pituitary-gonadal axis.

Nuttall, Mark E., George B. Stroup, Paul W. Fisher, Daniel P. Nadeau, Maxine Gowen, and Larry J. Suva. Distinct mechanisms of action of selective estrogen receptor modulators in breast and osteoblastic cells. Am J Physiol Cell Physiol 279: C1550-C1557, 2000.--Raloxifene and idoxifene are selective estrogen receptor modulators (SERMs) that exhibit tissue-specific agonist or antagonist properties via interactions with the estrogen receptor (ER). Both compounds are similarly osteoprotective in the ovariectomized rat in vivo as assessed by measurement of bone mineral density, urinary pyridinium cross-links, and serum osteocalcin, suggesting a similar mechanism of action. However, we have identified a fundamental difference in this mechanism via the estrogen response element (ERE) in osteoblast-like cells. With the use of ERE-luciferase reporter constructs, raloxifene, like the complete ER-antagonist ICI-182780. acts as an antagonist via the ERE in osteoblastic cells. In contrast, idoxifene, like 17[Beta]-estrogen itself and 4-OH-tamoxifen, acts as an agonist in osteoblastic cells via an ER/ERE-mediated mechanism. Both ICI-182780 and raloxifene inhibited the ERE-dependent agonist activity of 17[Beta]-estradiol and idoxifene in osteoblastic cells. In contrast, in breast cells, raloxifene, idoxifene, 4-OH-tamoxifen, and ICI-182780 had no agonist activity and, indeed, raloxifene and idoxifene were potent antagonists of ERE-mediated 17[Beta]-estradiol action, indicating an ERE-dependent mode of action in these cells. Although these SERMs exhibit a similar antagonist activity profile in breast cells, they can be distinguished mechanistically in osteoblastic cells. raloxifene; selective estrogen receptor modulator; estrogen; bone; breast

Plant-derived estrogen analogs (phytoestrogens) may confer significant health advantages, including cholesterol lowering, antioxidant activity and possibly reduced cancer risk. However, concern has also been raised that phytoestrogens may be endocrine disrupters and major health hazards. We therefore assessed the effects of soy foods as rich sources of isoflavonoid phytoestrogens on LDL oxidation and sex hormone receptor activity. Hyperlipidemic subjects (n = 31) consumed two low fat metabolic diets for 1 mo in a randomized crossover study. Major differences between test and control diets were the increases in soy protein foods (33 g/d of soy protein) providing 86 mg/(2000 kcal [multiplied by] d) of isoflavones and the doubling of soluble fiber intake. Fasting blood samples were obtained at the start, wk 2 and wk 4; 24-h urine samples were collected at the end of each phase. Soy foods increased urinary isoflavone excretion in subjects consuming the test diet compared with the control diet (3.8 [+ or -] 0.7 vs. 0.0 [+ or -] 0.0 mg/d; P [is less than] 0.001). The test diet lowered oxidized LDL concentrations measured both as conjugated dienes in the LDL fraction (56 [+ or -] 3 vs. 63 [+ or -] 3 mmol/L, P [is less than] 0.001) and as the ratio of conjugated dienes to LDL cholesterol (15.0 [+ or -] 1.0 vs. 15.7 [+ or -] 0.9, P = 0.032), even in subjects already taking vitamin E (400-800 mg/d). No significant difference was detected in ex vivo sex hormone activity between urine samples from the test and control periods. In conclusion, consumption of high isoflavone foods was associated with reduced levels of circulating oxidized LDL, even in subjects taking vitamin E, with no evidence of increased urinary estrogenic activity. Soy consumption may reduce cardiovascular risk without increasing risk for hormone-dependent cancers.