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The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 8 3691-3695
Copyright © 2002 by The Endocrine Society

Original Article

Estrogen-Like Activity of Ginsenoside Rg1 Derived from Panax notoginseng

Robbie Y. K. Chan, Wen-Fang Chen, Aling Dong, Dean Guo and Man-Sau Wong

The Open Laboratory of Chirotechnology, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University (R.Y.K.C., W.-F.C., M.-S.W.), Hung Hom, Kowloon, Hong Kong, Peoples Republic of China; and School of Pharmaceutical Sciences, Peking University (A.D., D.G.), Beijing 100083, People’s Republic of China

Address all correspondence and requests for reprints to: Man-Sau Wong, Ph.D., The Open Laboratory of Chirotechnology, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, Peoples Republic of China. E-mail: . bcmswong{at}polyu.edu.hk

Abstract

Ginsenosides have demonstrated pharmacological effects in the central nervous, cardiovascular, and endocrine systems. We hypothesize that ginsenosides might mediate some of their actions by binding to the estrogen receptor, as they share many of the protective actions of estrogen in various physiological systems. The present study is aimed to determine whether ginsenoside Rg1 can act like an estrogen analog in stimulating human breast cancer cell growth as well as in the activation of estrogen response element-luciferase activity in HeLa cell. Rg1, but not its aglycone, stimulates [methyl-3H] thymidine incorporation in estrogen receptor-positive MCF-7 in a dose-dependent manner (10-15–10-7 M). The stimulation of MCF-7 cell proliferation by 3 x 10-13 M Rg1 can be blocked by 10-6 M of the estrogen antagonist ICI 182780. Moreover, Rg1 stimulates estrogen response element-luciferase reporter gene activity in HeLa cells with an optimal dose of 3 x 10-10 M. Such stimulation can also be blocked by 10-6 M ICI 182780. In addition, Rg1 has no effect on [methyl-3H]thymidine incorporation in estrogen receptor-negative human breast cancer cells (MDA-MB-231). Furthermore, Rg1 failed to displace the specific binding of [3H]17ß-estradiol to MCF-7 cell lysates, suggesting that no direct interaction of Rg1 with estrogen receptor is needed for its estrogenic action. Our results indicate that ginsenosides Rg1 has estrogen-like activity and should be classified as a novel class of potent phytoestrogen.

THE GINSENG ROOT is one of the precious traditional Chinese medicines that is widely studied in the west. It has a long history of safe use in China for more than 2000 yr as a tonic to combat stress agents. There are seven major species of ginseng, including Panax Ginseng C.A. Meyer, Panax quinquefolius L., and Panax notoginseng. Ginseng has been demonstrated pharmacological effects in the central nervous, cardiovascular, endocrine, and immune systems (1).

Ginsenoside Rg1 is a steroidal saponin of high abundance in ginseng. Ginsenosides are the most important active constituents identified in all species of ginseng (2). There are two major classes of ginsenosides, namely, the derivatives of either protopanaxatriol (Rg1, Rg2, Re, and Rf) or protopanaxadiol (Rb1, Rb2, Rc, and Rd). They possess four trans-ring rigid steroid skeleton with a modified side-chain at C20, whereas estradiol has no side-chain (3). A previous study demonstrated that ginsenoside Rg1 can trans-activate glucocorticoid response element-luciferase activity by binding to the glucocorticoid receptor (4).

Ginseng is known to have cardioprotective effects in which ginsenosides can induce vasodilation via the action of nitric oxide release (5, 6). Ginsenosides have been shown to have anticarcinogenic effects through a different mechanism, either by direct cytotoxic effects toward cancer cells or by induction of differentiation and inhibition of metastasis of cancer cells (7, 8, 9, 10). Ginsenoside Rg1 play a major role in modulating neurotransmission and prevent scopolamine-induced memory deficits by increasing cholinergic activity (11, 12, 13). It was also shown to have an immunomodulating effect and increased both humoral and cell-mediated immune responses (14, 15).

Estrogens play an important role in bone maintenance, in the central nervous system, and in the cardiovascular system (16, 17, 18). Estrogens carry out their action by binding to a high affinity nuclear receptor, the estrogen receptor (ER). Bound ER undergoes conformational change, interacts with chromatin, and modulates the transcription of target genes in estrogen-responsive tissues (19, 20, 21). Many naturally occurring compounds, such as flavonoids, coumestan derivatives, and lignans, are nonsteroidal agents that have demonstrated weak estrogenic activity (22, 23, 24). As ginsenosides are naturally derived triterpenoid and share many of the target tissues of estrogens, we hypothesize that ginsenosides might mediate some of their actions via the activation of ER. The present study was designed to determine whether ginsenoside Rg1 isolated from Panax notoginseng has estrogen-like activity. The ability of ginsenoside Rg1 to stimulate [3H]thymidine incorporation in two human breast cancer cell lines with and without ER expression (MCF-7 and MDA, respectively) was tested. In addition, their ability to stimulate ER-dependent gene transcription was studied using HeLa cells transfected with the estrogen response element (ERE)-luciferase construct. Our findings indicated that ginsenosides Rg1 is a novel class of potent phytoestrogen.

Materials and Methods

Purification of ginsenoside Rg1 from Panax notoginseng

The powder of roots of P. notoginseng was extracted using 70% ethanol three times. The extract was evaporated to dryness at less than 50 C under reduced pressure, and the residue was dissolved in water and extracted by aqueous butanol three times. The butanol extract was evaporated to dryness at less than 50 C under reduced pressure and then was subjected to chromatography on D101 resin, which was eluted by using a 0–100% gradient of water-ethanol mixture. After removal of solvent, the 50% ethanol was subjected to chromatography on silica gel. Rg1 was eluted from the column using CHCl3-MeOH-H2O (50:10:1). The purities of Rg1 and its aglycone were determined by HPLC and were found to be more than 99%. The structure of Rg1 is shown in Fig. 1Go.



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  		Figure 1. Chemical structure of ginsenoside Rg1.

 
Culture of ER-positive and -negative human breast cancer cell lines (MCF7 and MDA-MB-231)

MCF7 (no. HTB-22, ATCC, Manassas, VA) and MDA-MB-231 cells (no. HTB-26, ATCC) were routinely cultured in DMEM with 5% fetal bovine serum (FBS, Life Technologies, Inc., Gaithersburg, MD) at a confluence of less than 70%. Culture medium was shifted to phenol red-free DMEM supplemented with 1% charcoal-stripped FBS, 100 U/ml penicillin, and 100 µg/ml streptomycin (Life Technologies, Inc.) for 5 d before the cells were seeded in a 96-well microtiter plate at a density of 2 x 104 cells/well. Cells were then treated with different concentrations of estrogen or with novel compounds with or without the ER antagonist ICI 182780 (Tocris, Bristol, UK). Drug treatments continued for 3 d, with the medium changed daily. Cells were cultured at 37 C in a humidified atmosphere of 95% air and 5% CO2.

[Methyl-3H]thymidine incorporation assay

The protocol is adopted from Congote (25) with some modifications. After drug treatment, cells were washed with serum-free medium once before adding serum-free medium containing 1 mCi/ml [methyl-3H]thymidine (Amersham Pharmacia Biotech, Little Chalfont, UK). Cells were returned to the incubator for 2 h before being chilled at 4 C for 15 min. Cells were then washed with ice-cold PBS twice. Two hundred microliters of ice-cold 0.75 M trichloroacetic acid (TCA)/well were added and incubated at 4 C for an additional 15 min. TCA was then removed, and 200 µl fresh TCA/well were added. Plates were baked at 75 C for 2 h. TCA from each well was transferred into a scintillation vial, and its radioactivity was measured by a scintillation counter.

Luciferase assay

A HeLa cell-based human ER{alpha}-luciferase reporter cell line (a gift from Dr. H. Gronemeyer, Strasbourg, France) was used to determine the degree of activation of ER induced by gensinoside. Cells were cultured in phenol-red free DMEM with 5% charcoal-stripped FBS, 100 U/ml penicillin, and 100 µg/ml streptomycin for 5 d before being seeded at a density of 3 x 105 cells/well in a 96-well plate. Rg1 at various concentrations, as indicated in Results, were used to treat cells for 24 h before they were washed with PBS and lysed in lysis buffer (Promega Corp., Madison, WI). Cells were frozen at –80 C and thawed to room temperature before the substrate luciferin (Promega Corp.) was added to the cell lysate. The amount of light produced, as a direct correlation of the degree of ER activation, was measured by TR717 microplate luminometer (PE Applied Biosystems, Foster City, CA).

ER binding assay

MCF-7 cells were cultured in phenol red-free DMEM supplemented with 5% charcoal-stripped FBS for 5 d before cellular protein was prepared. Cells were washed with ice-cold PBS twice and were scraped off the flasks using rubber policeman. Cells were suspended in PBS with 1 nM phenylmethylsulfonylfluoride and 1 ng/ml each of aprotinin and leupeptin. Cells were then passed through a 26-gauge needle 20 times for complete breakage. The cell lysate was centrifuged, and the resulting supernatant was saved and used for receptor binding assay. The final protein concentration in the binding assay was 1 mg/ml in a total volume of 500 µl containing different concentrations of [2,4,6,7-3H]estradiol (Amersham Pharmacia Biotech, Little Chalfont, UK) with or without a 500-fold excess of either nonlabeled estradiol or Rg1. Binding reactions were carried out at 4 C for 24 h before the lysate-ligand mixture was mixed thoroughly with dextran-coated charcoal. Protein was then separated from dextran-coated charcoal by centrifugation and transferred to scintillation vials for radioactivity measurement. Specific ligand binding was determined at each concentration of 17ß-estradiol by subtracting radioactive count in vials containing both radiolabeled and cold ligand [displacement count (DC)] from vials containing radiolabeled ligand only [total binding (TB)]. The percent specific ligand binding was calculated as: 100% x (TB-DC)/TB.

Statistical analysis

Data are reported as the mean ± SEM. The significance of differences between group means was determined by ANOVA when more than two groups were compared. Group means differing by a P values of 0.05 or less were considered statistically significant.

Results

Ginsenoside Rg1 stimulated [methyl-3H]thymidine incorporation in an ER-positive human breast cancer cell line (MCF7)

Rg1 increased [methyl-3H]thymidine incorporation in MCF7 cells in a dose-dependent manner. The concentration of Rg1 for maximal stimulation of MCF7 is approximately 3 x 10-13 M (Fig. 2Go; P < 0.005). The estimated EC50 of Rg1 in the [methyl-3H]thymidine incorporation assay is 0.05 pM. However, the up-regulation of [methyl-3H]thymidine incorporation in MCF7 cells was lost at high concentration (1–3 x 10-5 M) of Rg1 (Fig. 2Go). 17ß-Estradiol also increased [methyl-3H]thymidine incorporation in MCF7 cells in a dose-dependent manner, and the maximal stimulation of MCF7 cells occurred at 1 nM (Fig. 2Go). In contrast, the aglycone of Rg1 failed to stimulate increased [methyl-3H]thymidine incorporation in MCF7 cells (Fig. 2Go).



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  		Figure 2. Ginsenoside Rg1 stimulation of [3H]thymidine incorporation in human breast cancer cell line (MCF7). MCF7 cells were treated with increasing doses of Rg1, its aglycone, and 17ß-estradiol (E2) for 3 d before being labeled with [methyl-3H]thymidine. Rg1 and E2, but not the aglycone of Rg1, increased [3H]thymidine incorporation in MCF7 in a dose-dependent manner. Results were obtained from three different experiments and are expressed as the mean ± SEM (n = 6).

 
ER-dependent action of Rg1 in human breast cancer cell lines

To determine whether the up-regulation of thymidine incorporation by Rg1 in MCF-7 cells is mediated via the ER, cells were incubated with Rg1 in the presence or absence of the estrogen antagonist ICI 182780. ICI 182780 (10-7 M) completely blocked the increase in [methyl-3H]thymidine incorporation in MCF-7 by Rg1 and 17ß-estradiol (Fig. 3Go; P < 0.05). To determine the specificity of the activity of Rg1 in MCF-7 cells, the ability to increase [methyl-3H]thymidine uptake in an ER-negative human breast cancer cell line (MDA-MB-231) was tested. As expected, 17ß-estradiol did not increase [methyl-3H]thymidine incorporation in MDA-MB-231 cells. Rg1 did not increase [methyl-3H]thymidine incorporation in MDA-MB-231 cells at any concentration tested (3 x 10-13 to 3 x 10-7 M; data not shown).



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  		Figure 3. The ER antagonist ICI 182780 specifically blocks the action of ginsenoside Rg1 in MCF7 cells. MCF7 cells were treated with 3 x 10-13 M Rg1 or 10-9 M 17ß-estradiol (E2) with or without 10-6 M of the ER antagonist ICI 182780 for 3 d before they were labeled with [methyl-3H]thymidine. Results were obtained from three different experiments and are expressed as the mean ± SEM. *, Rg1 and E2 treatment significantly increases [methyl-3H]thymidine incorporation in MCF7 cells (vs. control, P < 0.01; n = 6). **, The actions of Rg1 and E2 in MCF7 cells were significantly inhibited by ICI 182780 (P < 0.01; n = 6).

 
Ginsenoside Rg1 stimulated ERE-dependent luciferase activity in HeLa cells

Rg1 and 17ß-estradiol increased ERE-dependent luciferase activity in a dose-dependent manner. The estimated EC50 of Rg1 in activation of ERE-dependent luciferase activity was 10 pM, and the concentration of Rg1 required for maximal stimulation of luciferase activity was 3 x 10-10 M (Fig. 4Go). Similar to the previous experiments, 10-6 M ICI 182780 efficiently blocked the stimulation of luciferase activity by 3 x 10-10 M Rg1 and 1 nM 17ß-estradiol (Fig. 5Go; P < 0.05).



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  		Figure 4. Ginsenoside Rg1 stimulates ER-dependent luciferase reporter gene activities in HeLa cells. HeLa cells were treated with increasing doses of Rg1 or 17ß-estradiol (E2) for 24 h before they were lysed and reacted with substrate luciferin. Arbitrary light units (ALU) were measured by luminometer. Results were obtained from three different experiments and are expressed as the mean ± SEM. Rg1 and E2 increase luciferase enzyme activities in a dose-dependent manner.

 


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  		Figure 5. The ER antagonist ICI 182780 specifically blocks the stimulation of luciferase activities by ginsenoside Rg1 in HeLa cells. HeLa cells were treated with 3 with 10-10 M Rg1 or 10-9 M 17ß-estradiol (E2) with or without 10-6 M ICI 182780 for 24 h before they were lysed and reacted with substrate luciferin. Arbitrary light units (ALU) were measured by luminometer. Rg1 and E2 treatment significantly increased estrogen-dependent activation of luciferase gene transcription in HeLa cells (vs. control, P < 0.01; n = 3). **, ICI 182780 specifically blocked the actions of Rg1 and E2 in HeLa cells (P < 0.01; n = 3).

 
Receptor binding assay

The binding of [3H]17ß-estradiol to MCF-7 cell lysates in the presence and absence of a 500-fold excess of cold Rg1 and 17ß-estradiol was determined. In the case of 17ß-estradiol, a 500-fold excess of cold ligand was sufficient to displace the specific binding of [3H]17ß-estradiol from its receptor in MCF-7 cell lysates. Figure 6Go demonstrates the percent specific binding of 17ß-estradiol at different concentrations of 17ß-estradiol. In contrast, a 500-fold excess concentration of nonlabeled Rg1 failed to displace the specific binding of [3H]17ß-estradiol from its receptor, and hence, minimum specific binding of Rg1 to MCF-7 cells was demonstrated (Fig. 6Go).



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  		Figure 6. ER binding assay. Receptor binding assays were carried as described in Materials and Methods. Total [3H]estradiol binding (TB) to the MCF-7 cellular protein was determined at different concentrations of radiolabeled ligand in the absence of nonlabeled competitor. Radioactive counts were also measured in the presence of a 500-fold molar excess of either nonlabeled estradiol or Rg1 attempting displacement of [3H]17ß-estradiol from ER (DC). The percent specific ligand binding was calculated based on the equation: 100% (TB - DC)/TB. The data are the mean of duplicate determinations, and the experiment was repeated twice. The specific binding of 17ß-estradiol increases with increasing doses of 17ß-estradiol. No specific binding of Rg1 to ER was found at any concentration of 17ß-estradiol tested.

 
Discussion

The present study clearly indicates that ginsenoside Rg1 can mediate its activities through the activation of ER in both human breast cancer cells (MCF-7) as well as human endometrial cells (HeLa). Its activities in both cell lines can be specifically blocked by treatment with the estrogen antagonist ICI 182780. In contrast to other phytoestrogens that require a high effective concentration for their action (micromolar), Rg1 can mediate their actions at a very low concentration (picomolar range). Thus, our results showed that Rg1 is a novel class of potent phytoestrogen.

Ginseng roots have multiple pharmacological actions (1, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15) and have been used by traditional Chinese medicinal practitioners in the treatment of cardiovascular diseases and cancer as well as in improving overall stress tolerance. Recently, due to the increase in worldwide popularity of alternative medicine in the prevention and treatment of diseases, the worldwide consumption of ginseng roots or extract is on the rise. Although many studies have been designed to study the pharmacological action of ginseng, the detailed mechanism of the action of ginseng extract has yet to be determined. The issue is complicated by the fact that there are more than 7 species of ginseng, which contain more than 30 ginsenosides and many other active ingredients (1). The pharmacological effects of each species might be determined by the type and specific interaction of each type of ginsenoside found.

In the present study we attempt to study the mechanism of action of one of the most abundant ginsenosides found in ginseng, namely ginsenoside Rg1. We hypothesize that as ginseng shares many of the target organs of estrogen, including brain and cardiovascular system, it might have estrogen-like properties and mediate its action via the activation of ER. Rg1 has been previously shown to interact with glucocorticoid receptor (4) and was chosen for the present study. Rg1 has a steroid backbone and contains two molecules of glucose at its 6th and 18th positions. Our study shows that the aglycone of Rg1 failed to stimulate the uptake of [3H]thymidine uptake in MCF-7, suggesting that these two glucose molecules are essential for the estrogenic action of Rg1. Our results showed that the activity of Rg1 require the presence of ER, as breast cancer cells (MDA-MB-231) failed to respond to treatment with Rg1. The action of Rg1 in MCF-7 and HeLa cells can be specifically blocked by treatment with ER antagonist (ICI 182780), providing further support for the role of activated ER in mediating its action in these cells.

The steroid backbone of Rg1 makes it a suitable candidate to interact and activate steroid receptors, such as glucocorticoid and estrogen receptors. However, to our surprise, the results in the present study showed that Rg1 does not interact directly with ER, as demonstrated by its inability to displace specific binding of [3H]17ß-estradiol to ER. The present study indicated that Rg1 could activate ER and trans-activate transcription of the luciferase gene without direct interaction with ER.

Dietary phytoestrogens have been the focus of investigations for their potential beneficial effects on cancer prevention and treatment of postmenopausal syndromes. Current lists of dietary phytoestrogen include isoflavones (22, 23, 24), coumestans (22, 23, 24), lignans (22, 23, 24), resveratrol (26), and 8-prenylnaringenin (27). The relative affinities of these compounds toward ERis in the millimolar to micromolar range, whereas the effective concentration of Rg1 in the stimulation of MCF7 cell growth and ERE-dependent luciferase activity is in the picomolar range. The latter clearly indicates that Rg1 is the most potent phytoestrogen identified to date. The fact that Rg1 does not directly interact with ER makes it an even more interesting phytoestrogen, as it might involve the activation of other signaling pathways that eventually lead to ER activation in both MCF-7 and HeLa cells. Nevertheless, Rg1 shares characteristics with other phytoestrogens in that it stimulates ER-dependent human breast cancer cell growth at low, but not high, concentrations. A previous report indicated that Rg1 can down-regulate glucocorticoid receptor content; thus, the reduced in action of Rg1 at high concentration might be mediated by a decreasing ER content in these cells. The exact mechanism involved in the dose-dependent change in activity as well as activation of ER without direct interaction will await further study.

Punnonen and Lukkola (28) reported previously that extract containing ginseng saponins can compete with estradiol and progesterone for binding to human myometrial cytosol. However, the exact components in the saponin fraction that contribute to the displacement of estradiol and progesterone binding have not been determined. Our findings indicates that Rg1, which is one of the most abundant ginsenosides in ginseng, might be a candidate. We are currently in the process to determine whether other ginsenosides can interact with the ER and mediate estrogen-dependent actions.

The discovery of the estrogen-like activity of Rg1 helps in understanding the miracle action of ginseng in the prevention and treatment of many diseases. The potential application of Rg1 in the treatment of estrogen-dependent symptoms, such as found in postmenopausal women, will await further detailed study on its potential risk of contributing to the development of breast and endometrial cancers. It should be noted that ginseng extract also contains many other ginsenosides that might contribute to either a synergistic or antagonistic effect of Rg1 on its target receptor. Future studies will be needed to clarify the complex interactions among the different ginsenosides that are naturally found in ginseng root.

Acknowledgments

Footnotes

This work was supported by the Areas of Excellence Scheme Established under the University Grants Committee of the Hong Kong Special Administrative Region, China (AOE/P-10/01), the Area of Strategic Development Grant from Hong Kong Polytechnic University, and the Central Allocation Grant from the Research Committee of Hong Kong Polytechnic University (GYC81).

Abbreviations: DC, Displacement count; ER, estrogen receptor; ERE, estrogen response element; FBS, fetal bovine serum; TB, total binding; TCA, trichloroacetic acid.

Received October 2, 2001.

Accepted April 17, 2002.

References

  1. Attele AS, Wu JA, Yuan CS 1999 Ginseng Pharmacology multiple constituents and multiple actions. Biochem Pharmacol 58:1685–1693[CrossRef][Medline]
  2. Banthorpe DV 1994 Terpenoids. In: Mann J, eds. Natural products. Essex: Longman Scientific and Technical; 331–339
  3. Shibata S, Tanaka O, Shoji J, Saito H 1985 Chemistry and pharmacology of Panax. In: Wagner H, Hikino H, Farnsworth NR, eds. Economic and medicinal plant research. New York: Academic Press; vol 1:217–284
  4. Lee YJ, Chung E, Lee KY, Lee YH, Huh B, Lee SK 1997 Ginsenoside-Rg1, one of the major active molecules from Panax ginseng, is a functional ligand of glucocorticoid receptor. Mol Cell Endocrinol 133:135–140[CrossRef][Medline]
  5. Gillis CN 1997 Panax ginseng pharmacology: a nitric oxide link? Biochem Pharmacol 54:1–8[CrossRef][Medline]
  6. Chen X 1996 Cardiovascular protection by ginsenosides and their nitric oxide releasing action. Clin Exp Pharmacol Physiol 23:728–732[Medline]
  7. Ota T, Fujikawa-Yamamoto K, Zong ZP, Yamazaki M, Odashima S, Kitagawa I, Abe H, Arichi S 1987 Plant-glycoside modulation of cell surface related to control of differentiation in cultured B16 melanoma cells. Cancer Res 47:3863–3867[Abstract/Free Full Text]
  8. Wakabayashi C, Murakami K, Hasegawa H, Murata J, Saiki I 1998 An intestinal bacterial metabolite of ginseng protopanaxafiol saponins has the ability to induce apoptosis in tumor cells. Biochem Biophys Res Commun 246:725–730[CrossRef][Medline]
  9. Mochizuki M, Yoo YC, Matsuzawa K, Sato K, Saiki U, Tono-Oka S, Samukawa KI, Azuma I 1995 Inhibitory effect of tumor metastasis in mice by saponins, ginsenoside-Rb2, 20(R)- and 20(S)-ginsenoside-Rg3, of Red ginseng. Biol Pharm Bull 18:1197–1202[Medline]
  10. Kim YS, Kim DS, Kim SI 1998 Ginsenoside Rh2 and Rh3 induce differentiation of HL-60 cells into granulocytes: modulation of protein kinase C isoforms during differentiation by ginsenoside Rh2. Int J Biochem Cell Biol 30:327–338[CrossRef][Medline]
  11. Saito H, Tsuchiya M, Naka S, Takagi K 1977 Effect of Panax ginseng root on conditioned avoidance response in rats. Jpn J Pharmacol 27:509–516[Medline]
  12. Tsang D, Yeung HW, Tso WW, Peck H 1985 Ginseng saponins: Influence on neurotransmitter uptake in rat brain synaptosomes. Planta Med 3:221–224
  13. Yamaguchi Y, Higashi M, Kobayashi H 1996 Effects of oral and intraventricular administration of ginsenosides Rg1 on the performance impaired by scopolamine in the rats. Biomed Res 17:487–490
  14. Kim JY, Germolec DR, Luster MI 1990 Panax ginseng as a potential immunomodulator: studies in mice. Immunopharmacol Immunotoxicol 12:257–276[Medline]
  15. Kenarova B, Neychev H, Hadjiivanova C, Petkov VD 1990 Immunomodulating activity of ginsenoside Rg1 from Panax ginseng. Jpn J Pharmacol 54:447–454[Medline]
  16. Felson DT, Zhang T, Hannan MT, Kiel DP, Wilson PW, Anderson JJ 1993 The effect of postmenopausal estrogen therapy on bone density in elderly women. N Engl J Med 329:1141–1146[Abstract/Free Full Text]
  17. Birge SJ 1997 The role of estrogen in the treatment and prevention of dementia. Am J Med 103:1S–50S
  18. Sudhir K, Komesaroff PA 1999 Cardiovascular actions of estrogens in men. J Clin Endocrinol Metab 84:3411–3415[Free Full Text]
  19. Brzozowski A, Pike A, Dauter Z, Hubbard R, Bonn T, Engstrom O, Ohman L, Greene G, Gustafsson J and Carlquist M 1997 Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 389:753–758[CrossRef][Medline]
  20. Kumar V, Green S, Stack G, Berry M, Jin JR, Chambon P 1987 Functional domains of the human estrogen receptor. Cell 51:941–951[CrossRef][Medline]
  21. Paech K, Webb P, Kuiper GG et al. 1997 Differential ligand activation of estrogen receptors: ER and ER at AP1 sites. Science 277:1508–1510[Abstract/Free Full Text]
  22. Tham DM, Gardner CD, Haskell WL 1998 Potential health benefits of dietary phytoestrogens: a review of the clinical, epidemiological, and mechanistic evidence. J Clin Endocrinol Metab 83:2223–2235[Abstract/Free Full Text]
  23. Cassidy A 1999 Potential tissue selectivity of dietary phytoestrogens and estrogens. Curr Opin Lipidol 10:47–52[CrossRef][Medline]
  24. Murkies AL, Wilcox G, Davis SR 1998 Phytoestrogens. J Clin Endocrinol Metab 83:297–303[Abstract/Free Full Text]
  25. Congote LF 1987 Effects of insulin-like growth factor I, platelet-derived growth factor, fibroblast growth factor, and transforming growth factor-ß on thymidine incorporation into fetal liver cells. Exp Hematol 15:936–941[Medline]
  26. Gehm BD, McAndrews JM, Chien PY, Jameson JL 1997 Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor. Proc Natl Acad Sci USA 94:14138–14143[Abstract/Free Full Text]
  27. Milligan SR, Kalita JC, Heyerick A, Rong H, De Cooman L, De Keukeleire D 1999 Identification of a potent phytoestrogen in hops (Humulus lupulus L.) and beer. J Clin Endocrinol Metab 83:2249–2252
  28. Punnonen R, Lukola A 1980 Oestrogen-like effect of ginseng. Br Med J 281:1110



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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals