Estrogen Balancing for Women and Men:Why Females and Males Should Consider Phytonutrient Support
Nieske Zabriskie, ND
Estrogen is a hormone typically associated with female health. Estrogen, however, also plays a lesser-known role in male health. The increasing level of environmental estrogens such as estrogen-mimicking pesticides along with a tendency for males to convert testosterone into estrogen, indicates that a discussion about balancing estrogen levels in the body is equally important to both sexes.
In men, the conversion of testosterone to estrogen plays a role in the development of prostate cancer. This tendency was demonstrated in animal models, where the addition of estrogen to testosterone significantly increased the incidence of prostate cancer. In addition, testosterone and other androgens may increase prostate cancer progression. This evidence suggests that it is the conversion of androgens to estrogens by aromatase that may be a causal factor in cancer initiation and that testosterone induces tumor promotion after the initial insult. This same study also showed that estrogen caused DNA damage in prostate cells, which can lead to the development of cancer at the exact location of the damage.1 Furthermore, the active testosterone metabolite 5-alpha-dihydrotestosterone, which cannot be aromatized to estrogen, is not known to induce prostate cancer, supporting a critical role of estrogen in prostate carcinogenesis.1
In women, a substantial amount of research has shown that estrogen metabolism is strongly associated with hormone-related cancers such as breast cancer. Estrogen, via its binding to the estrogen receptor, plays an important role in breast cancer cell proliferation and tumor development.
Estrogen can be metabolized through either beneficial or harmful biochemical pathways. The optimal pathway breaks down estrogen into 2-hydroxyestrone. Metabolizing estrogen via this pathway decreases hormone related cancer risk. The other pathway metabolizes estrogen to the carcinogenic products 16-hydroxyestrone and to a lesser extent 4-hydroxyestrone. An elevated ratio of these metabolites to the preferential 2-hydroxyestrone metabolites in women is associated with increased risk of invasive breast cancer.2
In both men and women, hormone balance is also related to the function of the aromatase enzyme. This enzyme is found in adipose tissue, muscle, breast tissue, ovaries, brain, the prostate and malignant breast tumors. Aromatase is the rate-limiting step in estrogen metabolism. This enzyme converts the androgens testosterone and androstenedione to the estrogens estradiol and estrone. In post-menopausal women, aromatase in adipose tissue is the primary source of circulating estrogens.
Modulation of hormone levels and activity is an important avenue for overall health. Therefore, in this article, I will discuss select phytonutrients that research indicates can favorably affect estrogen and androgen metabolism.
Indole-3-carbinol(I3C) and Diindolylmethane (DIM)
Cruciferous vegetables of the Brassica genus include cabbage, broccoli, cauliflower, radishes, parsnips, kale, and Brussels sprouts. Increased intake of cruciferous vegetables has been shown to decrease overall cancer risk.3 One of the constituents found in these vegetables, indole-3-carbinol (I3C), has been widely studied as a potential chemo-preventative and chemotherapeutic agent. It increases estrogen metabolism via the beneficial 2-hydroxylation pathway in humans from 29 percent to over 45 percent.4 Increasing the 2-hydroxylation pathway decreases the activity of the other, more harmful pathways. Furthermore, 2-hydroxylation end products decrease cell proliferation and increase apoptosis, or programmed cell death, which are important in the prevention of cancer. I3C also increases the expression of the well-known breast cancer suppression gene BRCA1. Additionally, I3C inhibits the activation of estrogen receptors by estradiol, which may prevent estrogen-enhanced cancers.5
I3C also protects against cervical cancer. Estrogen promotes development of cervical cancer in cells infected with high-risk human papillomaviruses (HPV). I3C and 2-hydroxyestrone inhibited the estrogen-increased expression of the HPV cancer-promoting genes.6 Evidence also demonstrates that I3C is a potent scavenger of free-radicals,7 highly reactive species that cause damage in the body and lead to aging, degenerative diseases, and cancer.
I3C is acid-catalyzed in the stomach into diindolylmethane (DIM). DIM is believed to be the active beneficial constituent in I3C and cruciferous vegetables. Both I3C and DIM induce biochemical pathways to metabolize potential carcinogens. I3C has been shown to decrease the proliferation of numerous forms of cancer including breast cancer, prostate cancer, endometrial cancer, colon cancer, and leukemia. Animal studies have shown that long-term administration of I3C decreased spontaneous breast tumor development by 50 percent and endometrial tumors by 24 percent. Additionally, animal models show that supplementation with I3C prior to exposure of a known carcinogen decreased the development of breast tumors by 70-90 percent.8 Studies on human breast cancer cell lines show that DIM inhibits the growth of both estrogen-dependent and estrogen-independent cancer cells by approximately 60 percent. This study also showed that DIM binds to the estrogen receptors in these cells, inhibiting the binding of estradiol.9 Other evidence shows that I3C decreases both the growth of blood supply to cancer cells and the spread of the cancerous cells locally and that it protects the liver from carcinogens.10
Another interesting property of DIM is that it exhibits anti-androgenic activity. Research shows that DIM inhibits dihydyrotestosterone (DHT) from binding to androgen receptors in androgen-dependent human prostate cancer cells, decreasing the induction of DNA synthesis. DIM also decreased levels of prostate specific antigen (PSA). This protein is frequently measured to evaluate prostate cancer risk. Additional research has shown that DIM induces cell-cycle arrest and apoptosis in prostate cancer cells as well as by regulating several genes.11
Resveratrol
Resveratrol is a natural polyphenol found in high concentrations in red grape skins, berries, and peanuts. It is found in high concentration in the diet in red wine and red grape juice. Resveratrol is widely studied due to its antioxidant, anti-inflammatory, anticancer and anti-aging properties.
Studies with resveratrol indicate that this polyphenol inhibits the activity of aromatase in breast cancer cells, a particularly important fact considering aromatase is expressed at a higher level in breast cancer tissue than in surrounding healthy tissue. In fact, resveratrol inhibits the conversion of estrogen and decreases the synthesis of the aromatase enzyme, thus indicating that it may support the health of individuals concerned about breast cancer.12 Research also shows that red wine extracts reversed aromatase-induced increased tissue size and other neoplastic changes in breast tissue.13 Research indicates that resveratrol also is effective at preventing several stages of carcinogenesis. It decreases tumor initiation, promotion, and progression, and induces apoptosis in many types of cancer cells.14
Conclusion
Balancing estrogen levels is essential for optimizing overall health in both women and men. A substantial amount of research is being done to identify potential phytonutrients—such as indole-3-carbinol (I3C), diindolylmethane (DIM) and resveratrol—that may modulate estrogenic activity. These phytonutrients provide exciting new avenues to pursue in the regulation of hormonal health.
References:1. Bosland MC. Sex steroids and prostate carcinogenesis: integrated, multifactorial working hypothesis. Ann N Y Acad Sci. 2006 Nov;1089:168-76.
2. Muti P, Bradlow HL, Micheli A, Krogh V, Freudenheim JL, Schunemann HJ, Stanulla M, Yang J, Sepkovic DW, Trevisan M, Berrino F. Estrogen metabolism and risk of breast cancer: a prospective study of the 2:16alpha-hydroxyestrone ratio in premenopausal and postmenopausal women. Epidemiology. 2000 Nov;11(6):635-40.
3. Keck AS, Finley JW. Cruciferous vegetables: cancer protective mechanisms of glucosinolate hydrolysis products and selenium. Integr Cancer Ther 2004 Mar;3(1):5-12.
4. Michnovicz JJ, Bradlow HL. Induction of estradiol metabolism by dietary indole-3-carbinol in humans. J Natl Cancer Inst. 1990 Jun 6;82(11):947-9.
5. Meng Q, Yuan F, Goldberg ID, Rosen EM, Auborn K, Fan S. Indole-3-carbinol is a negative regulator of estrogen receptor-alpha signaling in human tumor cells. J Nutr. 2000 Dec;130(12):2927-31.
6. Yuan F, Chen DZ, Liu K, Sepkovic DW, Bradlow HL, Auborn K. Anti-estrogenic activities of indole-3-carbinol in cervical cells: implication for prevention of cervical cancer. Anticancer Res. 1999 May-Jun;19(3A):1673-80.
7. Arnao MB, Sanchez-Bravo J, Acosta M. Indole-3-carbinol as a scavenger of free radicals. Biochem Mol Biol Int 1996 Aug;39(6):1125-34.
8. Leong H, Firestone GL, Bjeldanes LF. Cytostatic effects of 3,3’-diindolylmethane in human endometrial cancer cells result from an estrogen receptor-mediated increase in transforming growth factor-alpha expression. Carcinogenesis. 2001 Nov;22(11):1809-17.
9. Chang YC, Riby J, Chang GH, Peng BC, Firestone G, Bjeldanes LF. Cytostatic and antiestrogenic effects of 2-(indol-3-ylmethyl)-3,3’-diindolylmethane, a major in vivo product of dietary indole-3-carbinol. Biochem Pharmacol. 1999 Sep 1;58(5):825-34.
10. Aggarwal BB, Ichikawa H. Molecular targets and anticancer potential of indole-3-carbinol and its derivatives. Cell Cycle. 2005 Sep;4(9):1201-15. Epub 2005 Sep 6.
11. Sarkar FH, Li Y. Indole-3-carbinol and prostate cancer. J Nutr. 2004 Dec;134(12 Suppl):3493S-3498S.
12. Wang Y, Lee KW, Chan FL, Chen S, Leung LK. The red wine polyphenol resveratrol displays bilevel inhibition on aromatase in breast cancer cells. Toxicol Sci. 2006 Jul;92(1):71-7. Epub 2006 Apr 11.
13. Eng ET, Williams D, Mandava U, Kirma N, Tekmal RR, Chen S. Anti-aromatase chemicals in red wine. Ann N Y Acad Sci. 2002 Jun;963:239-46.
14. Jiang H, Zhang L, Kuo J, Kuo K, Gautam SC, Groc L, Rodriguez AI, Koubi D, Hunter TJ, Corcoran GB, Seidman MD, Levine RA. Resveratrol-induced apoptotic death in human U251 glioma cells. Mol Cancer Ther. 2005 Apr;4(4):554-61
In men, the conversion of testosterone to estrogen plays a role in the development of prostate cancer. This tendency was demonstrated in animal models, where the addition of estrogen to testosterone significantly increased the incidence of prostate cancer. In addition, testosterone and other androgens may increase prostate cancer progression. This evidence suggests that it is the conversion of androgens to estrogens by aromatase that may be a causal factor in cancer initiation and that testosterone induces tumor promotion after the initial insult. This same study also showed that estrogen caused DNA damage in prostate cells, which can lead to the development of cancer at the exact location of the damage.1 Furthermore, the active testosterone metabolite 5-alpha-dihydrotestosterone, which cannot be aromatized to estrogen, is not known to induce prostate cancer, supporting a critical role of estrogen in prostate carcinogenesis.1
In women, a substantial amount of research has shown that estrogen metabolism is strongly associated with hormone-related cancers such as breast cancer. Estrogen, via its binding to the estrogen receptor, plays an important role in breast cancer cell proliferation and tumor development.
Estrogen can be metabolized through either beneficial or harmful biochemical pathways. The optimal pathway breaks down estrogen into 2-hydroxyestrone. Metabolizing estrogen via this pathway decreases hormone related cancer risk. The other pathway metabolizes estrogen to the carcinogenic products 16-hydroxyestrone and to a lesser extent 4-hydroxyestrone. An elevated ratio of these metabolites to the preferential 2-hydroxyestrone metabolites in women is associated with increased risk of invasive breast cancer.2
In both men and women, hormone balance is also related to the function of the aromatase enzyme. This enzyme is found in adipose tissue, muscle, breast tissue, ovaries, brain, the prostate and malignant breast tumors. Aromatase is the rate-limiting step in estrogen metabolism. This enzyme converts the androgens testosterone and androstenedione to the estrogens estradiol and estrone. In post-menopausal women, aromatase in adipose tissue is the primary source of circulating estrogens.
Modulation of hormone levels and activity is an important avenue for overall health. Therefore, in this article, I will discuss select phytonutrients that research indicates can favorably affect estrogen and androgen metabolism.
Indole-3-carbinol(I3C) and Diindolylmethane (DIM)
Cruciferous vegetables of the Brassica genus include cabbage, broccoli, cauliflower, radishes, parsnips, kale, and Brussels sprouts. Increased intake of cruciferous vegetables has been shown to decrease overall cancer risk.3 One of the constituents found in these vegetables, indole-3-carbinol (I3C), has been widely studied as a potential chemo-preventative and chemotherapeutic agent. It increases estrogen metabolism via the beneficial 2-hydroxylation pathway in humans from 29 percent to over 45 percent.4 Increasing the 2-hydroxylation pathway decreases the activity of the other, more harmful pathways. Furthermore, 2-hydroxylation end products decrease cell proliferation and increase apoptosis, or programmed cell death, which are important in the prevention of cancer. I3C also increases the expression of the well-known breast cancer suppression gene BRCA1. Additionally, I3C inhibits the activation of estrogen receptors by estradiol, which may prevent estrogen-enhanced cancers.5
I3C also protects against cervical cancer. Estrogen promotes development of cervical cancer in cells infected with high-risk human papillomaviruses (HPV). I3C and 2-hydroxyestrone inhibited the estrogen-increased expression of the HPV cancer-promoting genes.6 Evidence also demonstrates that I3C is a potent scavenger of free-radicals,7 highly reactive species that cause damage in the body and lead to aging, degenerative diseases, and cancer.
I3C is acid-catalyzed in the stomach into diindolylmethane (DIM). DIM is believed to be the active beneficial constituent in I3C and cruciferous vegetables. Both I3C and DIM induce biochemical pathways to metabolize potential carcinogens. I3C has been shown to decrease the proliferation of numerous forms of cancer including breast cancer, prostate cancer, endometrial cancer, colon cancer, and leukemia. Animal studies have shown that long-term administration of I3C decreased spontaneous breast tumor development by 50 percent and endometrial tumors by 24 percent. Additionally, animal models show that supplementation with I3C prior to exposure of a known carcinogen decreased the development of breast tumors by 70-90 percent.8 Studies on human breast cancer cell lines show that DIM inhibits the growth of both estrogen-dependent and estrogen-independent cancer cells by approximately 60 percent. This study also showed that DIM binds to the estrogen receptors in these cells, inhibiting the binding of estradiol.9 Other evidence shows that I3C decreases both the growth of blood supply to cancer cells and the spread of the cancerous cells locally and that it protects the liver from carcinogens.10
Another interesting property of DIM is that it exhibits anti-androgenic activity. Research shows that DIM inhibits dihydyrotestosterone (DHT) from binding to androgen receptors in androgen-dependent human prostate cancer cells, decreasing the induction of DNA synthesis. DIM also decreased levels of prostate specific antigen (PSA). This protein is frequently measured to evaluate prostate cancer risk. Additional research has shown that DIM induces cell-cycle arrest and apoptosis in prostate cancer cells as well as by regulating several genes.11
Resveratrol
Resveratrol is a natural polyphenol found in high concentrations in red grape skins, berries, and peanuts. It is found in high concentration in the diet in red wine and red grape juice. Resveratrol is widely studied due to its antioxidant, anti-inflammatory, anticancer and anti-aging properties.
Studies with resveratrol indicate that this polyphenol inhibits the activity of aromatase in breast cancer cells, a particularly important fact considering aromatase is expressed at a higher level in breast cancer tissue than in surrounding healthy tissue. In fact, resveratrol inhibits the conversion of estrogen and decreases the synthesis of the aromatase enzyme, thus indicating that it may support the health of individuals concerned about breast cancer.12 Research also shows that red wine extracts reversed aromatase-induced increased tissue size and other neoplastic changes in breast tissue.13 Research indicates that resveratrol also is effective at preventing several stages of carcinogenesis. It decreases tumor initiation, promotion, and progression, and induces apoptosis in many types of cancer cells.14
Conclusion
Balancing estrogen levels is essential for optimizing overall health in both women and men. A substantial amount of research is being done to identify potential phytonutrients—such as indole-3-carbinol (I3C), diindolylmethane (DIM) and resveratrol—that may modulate estrogenic activity. These phytonutrients provide exciting new avenues to pursue in the regulation of hormonal health.
References:1. Bosland MC. Sex steroids and prostate carcinogenesis: integrated, multifactorial working hypothesis. Ann N Y Acad Sci. 2006 Nov;1089:168-76.
2. Muti P, Bradlow HL, Micheli A, Krogh V, Freudenheim JL, Schunemann HJ, Stanulla M, Yang J, Sepkovic DW, Trevisan M, Berrino F. Estrogen metabolism and risk of breast cancer: a prospective study of the 2:16alpha-hydroxyestrone ratio in premenopausal and postmenopausal women. Epidemiology. 2000 Nov;11(6):635-40.
3. Keck AS, Finley JW. Cruciferous vegetables: cancer protective mechanisms of glucosinolate hydrolysis products and selenium. Integr Cancer Ther 2004 Mar;3(1):5-12.
4. Michnovicz JJ, Bradlow HL. Induction of estradiol metabolism by dietary indole-3-carbinol in humans. J Natl Cancer Inst. 1990 Jun 6;82(11):947-9.
5. Meng Q, Yuan F, Goldberg ID, Rosen EM, Auborn K, Fan S. Indole-3-carbinol is a negative regulator of estrogen receptor-alpha signaling in human tumor cells. J Nutr. 2000 Dec;130(12):2927-31.
6. Yuan F, Chen DZ, Liu K, Sepkovic DW, Bradlow HL, Auborn K. Anti-estrogenic activities of indole-3-carbinol in cervical cells: implication for prevention of cervical cancer. Anticancer Res. 1999 May-Jun;19(3A):1673-80.
7. Arnao MB, Sanchez-Bravo J, Acosta M. Indole-3-carbinol as a scavenger of free radicals. Biochem Mol Biol Int 1996 Aug;39(6):1125-34.
8. Leong H, Firestone GL, Bjeldanes LF. Cytostatic effects of 3,3’-diindolylmethane in human endometrial cancer cells result from an estrogen receptor-mediated increase in transforming growth factor-alpha expression. Carcinogenesis. 2001 Nov;22(11):1809-17.
9. Chang YC, Riby J, Chang GH, Peng BC, Firestone G, Bjeldanes LF. Cytostatic and antiestrogenic effects of 2-(indol-3-ylmethyl)-3,3’-diindolylmethane, a major in vivo product of dietary indole-3-carbinol. Biochem Pharmacol. 1999 Sep 1;58(5):825-34.
10. Aggarwal BB, Ichikawa H. Molecular targets and anticancer potential of indole-3-carbinol and its derivatives. Cell Cycle. 2005 Sep;4(9):1201-15. Epub 2005 Sep 6.
11. Sarkar FH, Li Y. Indole-3-carbinol and prostate cancer. J Nutr. 2004 Dec;134(12 Suppl):3493S-3498S.
12. Wang Y, Lee KW, Chan FL, Chen S, Leung LK. The red wine polyphenol resveratrol displays bilevel inhibition on aromatase in breast cancer cells. Toxicol Sci. 2006 Jul;92(1):71-7. Epub 2006 Apr 11.
13. Eng ET, Williams D, Mandava U, Kirma N, Tekmal RR, Chen S. Anti-aromatase chemicals in red wine. Ann N Y Acad Sci. 2002 Jun;963:239-46.
14. Jiang H, Zhang L, Kuo J, Kuo K, Gautam SC, Groc L, Rodriguez AI, Koubi D, Hunter TJ, Corcoran GB, Seidman MD, Levine RA. Resveratrol-induced apoptotic death in human U251 glioma cells. Mol Cancer Ther. 2005 Apr;4(4):554-61