LE Magazine December 2002
The New Hormone Replacement Therapy
Protection against osteoporosis
Vitamins D and K, calcium and load-bearing exercise help maintain bone. Estrogen is also beneficial. Some phytoestrogens have bone-building effects. Phytoestrogens in flaxseed don’t seem to work, but other lignans do. So do genistein, daidzein, biochanin, formononetin, coumestrol, and others. Typically found in soybeans and other plants, these phytoestrogens maintain bone as well as estrogen drugs without the side effects. It appears, however, that different phytoestrogens affect different types of bone differently. In a study on daidzein and genistein, daidzein maintained both cancellous and cortical bone, whereas genistein only maintained cortical. Synthetic estrogen (17b-ethinylestradiol) also only maintains cortical. (Cancellous bone is the spongy bone inside the cortical bone). Based on these studies, a mixture of phytoestrogens is probably the best bet for staving off osteoporosis. Biochemical studies on how phytoestrogens build bone are in agreement with studies in people. The findings of a study of 650 Chinese women, are similar to the findings of other studies where those who ingested the most phytoestrogens had strongest hip and spine bones. Studies also show that using phytoestrogens to maintain bone doesn’t increase the risk of endometrial cancer.
Genistein and cancer cells
Despite the overwhelming benefits of phytoestrogens, some people have become leery because some researchers have reported that one of the soy phytoestrogens, genistein, can act like estrogen. First, it’s important to realize that acting estrogenic can be a good thing, depending on the tissue. In bone, for example, estrogenic type activity maintains bone. In immune cells, it increases the ability of natural killer cells to kill cancer cells. Genistein does both of these things. But in breast tissue, estrogen is not desirable because it can promote the proliferation of cells.
Second, it’s important to remember that different phytoestrogens act differently. Most do not have any estrogenic activity whatsoever. Some, like genistein, can have weak activity in certain tissues.
The perception that phytoestrogens promote, rather than impede, cancer was created by experiments in one type of human breast cancer cell. These cells, known as MCF-7 human breast cancer cells can be made to grow in test tubes using nano amounts of genistein. There must be no other estrogen in the cells, and only the tiniest amounts of genistein can be used to make the experiment work. (It should be noted that the same amount of genistein impedes growth in a different type of human breast cancer that has no estrogen receptors and is not estrogen-responsive.) In these cell experiments, if the amount of genistein added to the cells is greater than the tiniest amount, it will impede growth, not promote it. And if the cancer is not already there, genistein will not cause it.
One research group has gone one step further, and transplanted the MCF-7 tumor cells into mice. They report that increasing amounts of genistein enhance tumor size. This contradicts the cell studies which show that increasing amounts of genistein reduce cell growth. Another group has done a very similar study using the same type of cells in mice. They report that increasing amounts of genistein block cancer growth and induce cell death. Neither study has been independently verified by outside researchers. Unfortunately, the negative findings on genistein have been extrapolated to all isoflavones and phytoestrogens in general, leading to the false impression that these beneficial plant compounds are dangerous. A new study has been done in a mouse that has the human equivalent of a genetic defect (neu, HER2) that causes some breast cancers. It shows that genistein can significantly delay cancer onset, and that an isoflavone mixture can lower metastasis by 25% (genistein didn’t in this study).
Studies in monkeys, the closest animal model to humans, show that soy phytoestrogens impede estrogen-driven cell proliferation. Researchers who have been studying for decades the effects of different types of estrogens on monkeys state flatly: “Soybean phytoestrogens are not estrogenic at dietary doses.”
The preponderance of evidence on soy phytoestrogens to date agrees with observational studies in humans showing that women who eat large amounts of phytoestrogens have the least estrogen in their bodies, and the lowest rate of breast cancer.
Other “Hormone Replacement” estrogens
|In the future, real hormone replacement therapy will be possible. It will involve understanding not only a hormone’s individual effects, but its combined effects with other hormones. Then, and only then, will real “hormone replacement” be achieved.|
Synthesized hormones that have the same chemical structure as the body’s own hormones appear to be free of some of the side effects associated with hormones that are foreign to the human body. Natural progesterone cream, for example, doesn’t lower “good” HDL-cholesterol like the synthetic progesterone in “Prempro” does. Natural progesterone also lowers blood pressure instead of elevating it, and helps heart function instead of hindering it. The same type of heart benefits are found in phytoestrogens as well.
In the future, real hormone replacement therapy will be possible. It will involve understanding not only a hormone’s individual effects, but its combined effects with other hormones. Then, and only then, will real “hormone replacement” be achieved. In the meantime, modern technology has made it possible for people to get the benefits of phytoestrogens in a concentrated and purified form. The preponderance of the evidence is that these plant compounds have multi-system benefits, including protection against menopause and other effects of aging. Women in other cultures prove it—phytoestrogens work. Note: For those women who have not found effective relief from menopausal symptoms, despite using varying combinations of phytoestrogens and DHEA, refer to the updated Female Hormone Replacement Protocol.
*Estrogen refers to that made by the body.
**For more on this, see the Our Stolen Future website.
***Figures from IARC CancerBase, Globocan 2000, see www-dep.iarc.fr
Adlercreutz H, et al. 1992. Dietary phytoestrogens and cancr: in vitro and in vivo studies. J Steroid Biochem Mol Biol 41:331-37.
Adlercreutz H, et al. 1987. Effect of dietary components, including lignans and phytoestrogens, on enterohepatic circulation and liver metabolism of estrogens and on sex hormone binding globulin (SHBG). J Steroid Biochem 27:1135-44.
Adlercreutz H, et al. 1993. Inhibition of human aromatase by mammalian lignans and isoflavonoid phytoestrogens. J Steroid Biochem 44:147-53.
Alhasan SA, et al. 2001. Genistein elicits pleiotropic molecular effects on head and neck cancer cells. Clin Cancer Res 7:4174-81.
Andersson A, et al. 1999. Exposure to exogenous estrogens in food: possible impact on human development and health. Eur J Endocrin 140:477-85.
Andrade PM, et al. 2002. Estrogen regulation of uterine genes in vivo detected by complementary DNA array. Horm Metab Res 34:238-44.
Anthony MS, et al. 1997. Soy protein versus soy phytoestrogens in the prevention of diet-induced coronary artery atherosclerosis of male cynomolgus monkeys. Arterioscler Thromb Vasc Biol 17:2524-31.
Barrett-Connor E, et al. 1990. Dehydroepiandrosterone sulfate and breast cancer risk. Cancer Res 50:6571-74.
Barrett-Connor E, et al. 1999. Endogenous levels of dehydroepiandrosterone sulfate, but not other sex hormones, are associated with depressed mood in older women: the Rancho Bernardo Study. J Am Geriatr Soc 47:685-91.
Bendridi N, et al. 2002. Intravenous injection of human sex steroid hormone-binding globulin in mouse decreases blood clearance rate and testicular accumulation of orally administered [2-125I]iodobisphenol A. Steroids 67:637-45.
Beyene Y, et al. 2001. Menopausal experiences and bone density of Mayan women in Yucatan, Mexico. Am J Human Biol 13:505-11.
Bloch M, et al. 1999. Dehydroepiandrosterone treatment of midlife dysthymia. Biol Psychiatry 45:1533-41.
Boccuzzi G, et al. 1993. Dehydroepiandrosterone entiestrogenic action through androgen receptor in MCF-7 human breast cancer cell line. Anticancer Res 13:2267-72.
Burow ME, et al. 2001. Phytochemical glyceolins, isolated from soy, mediate antihormonal effects through estrogen receptor alpha and beta. J Clin Endocrinol Metab 86:1750-8.
Campbell TC, et al. 1998. Diet, lifestyle, and the etiology of coronary artery disease: the Cornell China study. Am J Cardiol 82(10B):18T-21T.
Clarkson TB, et al. 2001. Inhibition of postmenopausal atherosclerosis progression, a comparison of the effects of conjugated equine estrogens and soy phytoestrogens. J Clin Endocrinol Metab 86:41-47.
Clifton-Bligh PB, et al. 2001. The effect of isoflavones extracted from red clover (Rimostil) on lipid and bone metabolism. Menopause 8:259-65.
Cline JM, et al. 2001. Assessment of hormonally active agents in the reproductive tract of female nonhuman primates. Toxicol Path 29:84-90.
Couillard S, et al. 1998. Effect of dehydroepiandrosterone and the antiestrogen EM-800 on growth of human ZR-75-1 breast cancer xenografts. J Natl Cancer Inst 90:772-78.
Dabrosin C, et al. 2002. Flaxseed inhibits metastasis and decreases extracellular vascular endothelial growth factor in human breast cancer xenografts. Cancer Lett 185:31-7.
Deodato B, et al. 1999. Cardioprotection by the phytoestrogen genistein in experimental myocardial ischaemia-reperfusion injury. Br J Pharmacol 128:1683-90.
Dorgan JF, et al. 1997. Relationship of serum dehydroepiandrosterone (DHEA), DHEA sulfate, and 5-androstene-3 beta, 17 beta-diol to risk of breast cancer in postmenopausal women. Cancer Epidem Biomarkers Prev 6:177-81.
Draper CR, et al. 1997. Phytoestrogens reduce bone loss and bone resorption in oophorectomized rats. J Nutr 127:1795-9.
Evans A. 2002. Hormone replacement therapy and mammographic screening. Clin Radiol 57:563-64.
Fang Z, et al. 2001. Estrogen depletion induces NaCl-sensitive hypertension in female spontaneously hypertensive rats. Am J Physiol Regul Integr Comp Physiol 281:R1934-39.
Filleur F, et al. 2001. Antiproliferative, anti-aromatase, anti 17beta-HSD and antioxidant activities of lignans isolated from Myristica argentea. Planta Med 67:700-4.
Fritz WA, et al. 2002. Dietary genistein downregulates androgen and estrogen receptor expression in the rat prostate. Mol Cell Endocrinol 186:89-99.
Gallus S, et al. 2002. Post-menopausal hormonal therapy and gallbladder cancer risk. Int J Cancer 99:762-3.
Genazzani AD, et al. 2001. Oral dehydroepiandrosterone supplementation modulates spontaneous and growth hormone-releasing hormone-induced growth hormone and insulin-like growth factor-1 secretion in early and late postmenopausal women. Fertil Steril 76:241-48.
Gibbons WE, et al. 1986. Biochemical and histologic effects of sequential estrogen/progestin therapy on the endometrium of postmenopausal women. Am J Obstet Gynecol 154:456-61.
Goodson WH, et al. 2002. Causes of physician delay in the diagnosis of breast cancer. Arch Intern Med 162:1343-48.
Helzlsouer KJ, et al. 1992. Relationship of prediagnostic serum levels of dehydroepiandrosterone and dehydroepiandrosterone sulfate to the risk of developing premenopausal breast cancer. Cancer Res 52:1-4.
Hong H, et al. 2002. Prediction of estrogen receptor binding for 58,000 chemicals using an integrated system of a tree-based model with structural alerts. Environ Health Perspect 110:29-36.
Hutchins AM, et al. 2001. Flaxseed consumption influences endogenous hormone concentrations in postmenopausal women. Nutr Cancer 39:58-65.
Ingram D, et al. 1997. Case-control study of phyto-oestrogens and breast cancer. [see comments]. Lancet 350:990-4.
Ishimi Y, et al. 1999. Selective effects of genistein, a soybean isoflavone, on B-lymphopoiesis and bone loss caused by estrogen deficiency. Endocrinology 140:1893-900.
Jenkins DJ, et al. 2000. Effect of soy protein foods on low-density lipoprotein oxidation and ex vivo sex hormones receptor activity–a controlled crossover trial. Metabolism 49:537-43.
Jin Z, et al. 2002. Soy isoflavones increase latency of spontaneous mammary tumors in mice. J Nutr 132:3186-90.
Key TJ, et al. 1990. Sex hormones in women in rural China and in Britain. Br J Cancer 62:631-6.
Kilkkinen A, et al. 2002. Use of oral antimicrobials decreases serum enterolactone concentration. Am J Epidemiol 155:472-7.
Kilkkinen A, et al. 2001. Determinants of serum enterolactone concentration. Am J Clin Nutr 73:1094-100.
de Kleijn MJ, et al. 2001. Intake of dietary phytoestrogens is low in postmenopausal women in the United States: the Framingham study (1-4). J Nutr 131:1826-32.
Lasco A, et al. 2001. Metabolic effects of dehydroepiandrosterone replacement therapy in postmenopausal women. Eur J Endocrinol 145:457-61.
Lord RS, et al. 2002. Estrogen metabolism and the diet-cancer connection: rationale for assessing the ratio of urinary hydroxylated estrogen metabolites. Altern Med Rev 7:112-29.
Lubet RA, et al. 1998. Modulation of methylnitrosourea-induced breast cancer in Sprague Dawley rats by dehydroepiandrosterone: dose-dependent inhibition, effects of limited exposure, effects on peroxisomal enzymes, and lack of effects on levels of Ha-Ras mutations. Cancer Res 58:921-26.
Lucas EA, et al. 2002. Flaxseed improves lipid profile without altering biomarkers of bone metabolism in postmenopausal women. J Clin Endocrinol Metab 87:1527-32.
Makela S, et al. 1995. Estrogen-specific 17 beta-hydroxysteroid oxidoreductase type 1 (E.C. 22.214.171.124) as a possible target for the action fo phytoestrogens. Proc Soc Exp Biol Med 208:51-9.
Martin MC, et al. 1993. Menopause without symptoms: the endocrinology of menopause among rural Mayan Indians. Am J Obstet Gynecol 168(6 P 1): 1839-43; discussion 1843-5.
Maume D, et al. 2001. Assessment of estradiol and its metabolites in meat. APMIS 109:32-8.
Mei J, et al. 2001. High dietary phytoestrogen intake is associated with higher bone mineral density in postmenopausal but not premanopausal women. J Clin Endocrinol Metab 86:5217-21.
Michael A, et al. 2000. Altered salivary dehydroepiandrosterone levels in major depression in adults. Biol Psychiatry 48:989-95.
Miodini P, et al. 1999. The two phyto-oestrogens genistein and quercetin exert different effects on oestrogen receptor function. Br J Cancer 80:1150-5.
Ottosson UB, et al. 1985. Subfractions of high-density lipoprotein cholesterol during estrogen replacement therapy: a comparison between progestogens and natural progesterone. Am J Obstet Gynecol 151:746-50.
Owen RW, et al. 2000. Identification of lignans as major components in the phenolic fraction of olive oil. Clin Chem 46:976-88.
Pawlikowski M, et al. 2002. Effects of six months melatonin treatment on sleep quality and serum concentrations of estradiol, cortisol, dehydroepiandrosterone sulfate, and somatomedin C in elderly women. Neuroendocrinol Lett Suppl 1:17-19.
Poirson-Bichat F, et al. 1997. Growth of methionine-dependent human prostate cancer (PC-3) is inhibited by ethionine combined with methionine starvation. Br J Cancer 75:1605-12.
Raineri M, et al. 2002. O-glycosylation of human sex hormone-binding globulin is essential for inhibition of estradiol-induced MCF-7 breast cancer cell proliferation. Mol Cell Endocrinol 189:135-43.
Rosano GM, et al. 2000. Natural progesterone, but not medroxyprogesterone acetate, enhances the beneficial effect of estrogen on exercise-induced myocardial ischemia in postmenopausal women. J Am Coll Cardiol 36:2154-59.
Rosenberg Z, et al. 2002. Flavonoids can block PSA production by breast and prostate cancer cell lines. Clin Chim Acta 317:17-26.
Rowland IR, et al. 2000. Interindividual variation in metabolism of soy isoflavones and lignans: influence of habitual diet on equol production by the gut microflora. Nutr Cancer 36:27-32.
Rylance PB, et al. 1985. Natural progesterone and antihypertensive action. Br Med J (Clin Res Ed) 290(6461)13-14.
Seow A, et al. 2002. Diet, reproductive factors and lung cancer risk among Chinese women in Singapore, evidence for a protective effect of soy in nonsmokers. Int J Cancer 97:365-71.
Shao Z, et al. 2000. [Genistein exerts multiple suppressive effects on human breast carcinoma cells]. Zhonghua Zhong Liu Za Zhi 22:362-5.
Shao ZM, et al. 1998. Genistein exerts multiple suppressive effects on human breast carcinoma cells. Cancer Res 58:4851-7.
Sonnenschein C, et al. 1998. An updated review of environmental estrogen and androgen mimics and antagonists. J Steroid Biochem Mol Biol 65:143-50.
Soto AM, et al. 1994. The pesticides endosulfan, toxaphene, and dieldrin have estrogenic effects on human estrogen-sensitive cells. Environ Health Perspect 102:380-83.
Soto AM, et al. 1991. p-Nonyl-phenol: an estrogenic xenobiotic released from “modified” polystyrene. Environ Health Perspect 92:167-73.
Stoll BA, et al. 1999. Dietary supplements of dehydroepiandrosterone in relation to breast cancer risk. Eur J Clin Nutr 53:771-75.
Takayanagi R, et al. 2002. Dehydroepiandrosterone (DHEA) as a possible source for estrogen formatoin in bone cells: correlation between bone mineral density and serum DHEA-sulfate concentration in postmenopausal women, and the presence of aromatase to be enhanced by 1,25-dihydroxyvitamin D3 in human osteoblasts. Mech Ageing Dev 123::1107-14.
Thiagarajan DG, et al. 1998. Prevention of precancerous colonic lesions in rats by soy flakes, soy flour, genistein and calcium. Am J Clin Nutr 68(6 Suppl):1394S-99.
Thompson LU, et al. 1996. Flaxseed and its lignan and oil components reduce mammary tumor growth at a late stage of carcinogenesis. Carcinogenesis 17:1373-6.
Torres-Sanchez L, et al. 2000. Food sources of phytoestrogens and breast cancer risk in Mexican women. Nutr Cancer 37:134-9.
Wolkowitz CM, et al. 1999. Double-blind treatment of major depression with dehydroepiandrosterone. Am J Psychiatry 156:646-69.
Yamauchi A, et al. 1996. Depression of dehydroepiandrosterone in Japanese diabetic men–comparison between non-insulin-dependent diabetes mellitus and impaired glucose tolerance. Eur J Endocrinol 135:101-4.
Zhang Y, et al. 1999. Daidzein and genisein glucuronides in vitro are weakly estrogenic and activate human natural killer cells at nutritionally relevant concentrations. J Nutr 129:399-405.
Zhou JR, et al. 1998. Inhibition of murine bladder tumorigenesis by soy isoflavones via alterations in the cell cycle, apoptosis, and angiogenesis. Cancer Res 58:5231-8.
Back to the Magazine Forum