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Soy IsoFlavones

Soy isoflavones (known as Glycine max) are phytoestrogens which are plant-derived nonsteroidal compounds from the pea (fabaceae) family that possess estrogen-like biological activity enabling them to bind to estrogen receptors. Soy isoflavones are commonly used for reduction of hot flashes and other menopausal symptoms, prevention of osteoporosis, and cardiovascular disease risk factor reduction. Epidemiological data also suggests that higher soy isoflavone consumption correlates with reduced risk for developing cancer and reduced cholesterol content. However, well-designed clinical trials are still required to investigate the effects of soy isoflavones on these conditions before definitive conclusions can be drawn. Soybeans (Glycine max) and soy products (eg. soy milk, soy nuts, tofu) are the richest sources of isoflavones in the human diet. Soy isoflavones found in dietary supplements are normally present in the form of the isoflavones genistein (most abundant in soy), daidzein, and glycitein (least abundant in soy). In the West, dietary intake of isoflavones is generally lower due to low levels of consumed soy-derived foods. Natural intakes are higher (25-50 mg isoflavones daily) in traditional diets from Asian countries.

Dosing

Bone density

Doses of 80mg of soy isoflavones daily for 12 months have been studied and are associated with reductions in bone resorption (1). In subgroup analyses, significant reductions in markers of bone resorption were seen at doses less than 90 mg/day but not for doses greater than 90 mg/day (2).

Menopausal symptoms

Doses of 100-120 mg of soy isoflavones have been studied and shown to decrease the incidence of hot flushes in a majority of randomized controlled trials conducted (3). 100 mg of soy isoflavones daily for 4 months was used in an RCT examining the benefits of soy isoflavones on menopausal symptoms (4). In this study, the concentration of each capsule was 83.3 mg and composed of soy protein 50.3 mg (60%) and isoflavone 33.3 mg (40%) (4). The specific amount of genistein, daizein, and glycitein in aglycone form in each capsule was 23.3 mg, 6.2 mg, and 3.8 mg, respectively (4).

Standardization

Though sources vary, the percentages of soy isoflavones present in a standard soy isoflavone supplement reflect levels found in soybeans (genistin 50%, daidzin 38%, glycitin 12%) (28). A standard supplement formula consists of approximately 40% isoflavones (28).

Onset of Action

For skeletal related benefits in the prevention of osteoporosis, reductions in markers of bone resorption were seen in interventions that lasted up to 12 weeks (2). However, a double-blind, placebo controlled RCT involving 203 early post-menopausal women (aged 48-62 years) showed no statistical improvement for bone mineral density (BMD) over a 1 year period (1). Therefore, it may take up to 3 months to notice a reduction in bone resorption markers and possibly more than 1 year to see noticeable improvements in BMD.

For reductions in menopausal symptoms (hot flushes, night sweats), a double-blind RCT of 75 post-menopausal women (taking 70 mg soy isoflavones daily) conducted by Faure et al. demonstrated at least a 50% reduction in symptoms after a 16 week period (5). Another RCT performed by Han et al. showed that women taking 100 mg soy isoflavone daily showed a significant reduction in menopausal symptoms after 4 months (4). Therefore, it may take more than 3 months to see a 50% reduction in menopausal symptoms.

Mechanisms of action (MOA)

Menopausal MOA

The chemical structure of isoflavones is similar to that of endogenous estrogen allowing isoflavones to compete with estrogen for the same receptors and exert estrogenic and antiestrogenic effects (6). In the early menopause transition, there is a decrease in ovarian follicles (6). This leads to increased FSH levels that relatively preserve estrogen secretion (normal or high estradiol levels) but low luteal phase progesterone concentrations (6). Consumption of soy containing isoflavones has shown to increase plasma progesterone levels and decrease estrone and estradiol levels in females (6).

Osteoporosis MOA

Consumption of soy isoflavones increases the ratio of C-telopeptide to osteocalcin, indicating a greater rate of bone formation than bone resorption (6). The exact mechanism by which isoflavones alter bone remodeling is not completely understood (6). In vitro studies suggest that this effect may be due in part to their estrogenic activity because they act like SERMs (selective estrogen receptor modulators) (6). They exert both estrogen agonistic and antagonistic effects, depending on conditions at the estrogen receptor (6). Isoflavones have been reported to stimulate osteoblastic bone formation and inhibit osteoclastic bone resorption, thereby increasing bone mass (7). Recently, the soy isoflavone genistein has been found to increase the production of osteoprotogerin (OPG) from osteoblasts, a decoy factor that neutralizes the actions of RANKL, which is involved in promoting osteoclast activity (7).

Estrogen Receptor-Independent MOA’s

Soy isoflavones and their metabolites also have biological activities that are unrelated to their interactions with estrogen receptors (8). By inhibiting the synthesis and activity of certain enzymes involved in estrogen metabolism, soy isoflavones may alter the biological activity of endogenous estrogens and androgens (8). Soy isoflavones have also been found to inhibit tyrosine kinases which are enzymes that play critical roles in the signaling pathways that stimulate cell proliferation (9). Therefore, soy isoflavones may also have potential anticancer effects (9).

Evidence for osteoporosis prevention

Although rates of hip fractures are generally lower among Asian populations consuming soy foods than among Western populations, the evidence is not yet clear whether increasing soy isoflavone consumption in Western populations will prevent osteoporosis (8). A meta-analysis of 8 randomized controlled trials (RCTs) of short duration (≤ 6 months) assessed the effects of soy isoflavone intake on biochemical markers of bone resorption and formation; the results were inconsistent (2). Four of these RCTs in postmenopausal women showed that increasing soy isoflavone intake improved markers of bone resorption and formation or reduced bone loss (10–13), while the other four RCTs found no significant benefit (14–17). RCTs of longer duration are necessary to determine whether soy isoflavones can truly prevent losses in bone mineral density (BMD) or osteoporotic fracture. Two RCTs in postmenopausal women found that BMD losses over 6 months were significantly lower in the women supplemented with soy protein containing isoflavones versus placebo (milk protein) (15,18). However, two RCTs of longer duration (1 year) found no statistical difference in BMD loss in postmenopausal women under the same trial arms (12,19). In 2 year placebo-controlled RCT, Lydeking et al. demonstrated that daily intake of soymilk containing isoflavones significantly decreased BMD loss in the lumbar spine compared to placebo in postmenopausal women (20). Subjects were supplied with a total of 500 ml of soymilk/day supplying 17.5 g protein/d as divided servings – one glass in the morning and evening, respectively, with an aglycone isoflavone content of 76.0 mg/day for 500 mL (20). The soymilk was produced from 40% isoflavone-rich soybean extract (20). However a different 2 year double-blind, placebo-controlled RCT by Chen et al. found that BMD loss did not significantly differ between the same trial arms as above. (21) Chen et al. also showed that loss of BMC (bone mineral content) at the hip was lower over 1 year in Taiwanese women taking 80 mg/day of isolated soy isoflavones compared to placebo, but the difference was significant only in women who were four years post-menopause, had lower body weights (≤ median, 55.5 kg), or had lower calcium intakes (≤ median, 438 mg elemental Ca2+) (21). In this study, 8% (w/w) soy-derived isoflavones (expressed in aglycone form) were supplied by Acatris Holding B.V. (Giessen, The Netherlands) (21). The main isoflavone components of this product were daizein (46.4%), glycetein (38.8%), and genistein (14.7%) (21). Furthermore, 1 year open-labeled, self-controlled study of 43 post-menopausal Taiwanese women (median age <67 years) found that those consuming 100 mg/day of isolated soy isoflavones experienced no improvement over placebo (22). The isoflavone tablets used in the study were manufactured by Chia-Hsin Food and Synthetic Fiber, Taipei, Taiwan (22). Each tablet was made of 125 mg soy protein extracts containing 50 mg isoflavone (35.5 mg genistein and 14.5 daidzein) (22). Thus, while some scientific evidence shows that soy isoflavones have bone-sparing effects, it is unclear whether increasing intake will prevent or decrease the risk of osteoporotic fractures.

Evidence for menopausal symptoms

The concern over potential adverse effects from hormone replacement therapy (eg. stroke, breast cancer, pulmonary embolism) have led to increased interests for the use of non-conventional therapies such as soy isoflavones for women experiencing menopausal symptoms (23). A 2004 systematic review examined 10 RCTs of soy or soy isoflavones as monotherapy for perimenopausal symptoms and found that only 4 trials reported beneficial improvements in symptoms (24). A recent 2006 meta-analysis of 12 RCTs found that soy isoflavone supplementation was related to only a small reduction in the number of hot flushes and concluded that the benefit may be more apparent in women experiencing a higher number of flushes per day (25). A review by Williamson-Hughes et al. found that soy isoflavone supplements containing a greater content of genistein (≥15 mg) per treatment reported a statistically significant decrease in hot flush symptoms compared to products containing less than 15 mg of genistein (26). Recently, a 2008 placebo-controlled RCT of 96 healthy menopausal women found that those who produced the isoflavone metabolite equol experienced significant reductions in menopausal symptoms (hot flushes, excessive sweating) over placebo following soy isoflavone supplementation after 3 months (27). The women in this study took 3 grams of soy germ extract powder (SoyLife; Frutarom Belgium NV, Londerzeel, Belgium) twice a day for 6 months which was equivalent to 135 mg of isoflavones per day (27). One gram of powder contained 10.9 mg of daidzein, 2.85 mg of genistein, and 8.75 mg of glycitein (27). Equol is a non-steroidal estrogen that is metabolized from the soy isoflavone daidzein by intestinal flora and is thought to play a role in reducing the severity of menopausal symptoms by binding to the type β estrogen receptor (27). To date, studies on the effect of soy isoflavone consumption on menopausal symptoms have reported conflicting results.

Safety

Side effects

Taking soy isoflavones in the form of dietary supplements seems to be safe for most people when used short-term (up to six months) (28). The long-term effects of soy isoflavones on estrogen-sensitive tissues is unknown (28). Soy isoflavones can cause some mild side effects such as constipation, bloating, and nausea (29). Flatulence, loss of appetite, diarrhea, stomach cramps, and abdominal pain have also been suggested as potential side effects (29). In human studies, there was an overall decrease in systolic and diastolic blood pressure following use of soy isoflavones (28). In a case study, the use of a high-dose isoflavone supplement lead to a hypertensive crisis (28). In regards to renal effects, a higher risk of developing kidney stones has been shown to be a potential adverse effect (29).

Contraindications

Soy isoflavones should be avoided in patients allergic/hypersensitive to soy or soy-derived products or to any component of the product (29). The use of soy isoflavones is often discouraged in patients with hormone-sensitive malignancies such as breast, ovarian, or uterine cancer, due to concerns about possible estrogen-like effects (which may stimulate tumor growth) (29). Soy isoflavone supplementation should also be avoided in higher than dietary amounts in women who are pregnant or lactating, due to a lack of safety information (29). Food sources of soy isoflavones are likely safe in pregnancy and nursing when taken in standard dietary amounts (25-50 mg/day) (29). In children, high dietary amounts of soy isoflavones should also be avoided due to a lack of safety information (29).

Drug Interactions

Soy isoflavonoids should be used cautiously in patients taking antiplatelet or anticoagulant medications since isoflavones have shown to result in a decline in platelet thromboxane A2 receptor density, increasing the risk for bleeding (29). Patients using hormonal products should be cautioned since the soy isoflavone genistein binds to the estrogen receptor and may enhance acetylcholinesterase activity (30). Isoflavone supplements may have an additive hypotensive effect when used with antihypertensive agents; however isolated isoflavones have been shown to increase blood pressure in other human research (29). Soy isoflavones should also be used cautiously in patients with thyroid disorders or taking thyroid hormones since soy isoflavones may alter thyroxine, thyroid-stimulating hormone, and T3 levels, which may necessitate an increase in dose of thyroid hormone required by hypothyroid patients (29). Theoretically, antibiotics may reduce intestinal metabolism of isoflavones by their effect on intestinal bacterial flora, thus reducing the beneficial effects of isoflavones (29). Soy isoflavones should be used cautiously in patients with diabetes or taking hypoglycemic medications; women with high genistein intake had lower fasting insulin levels and lowered blood glucose in certain studies (29,31). A potential interaction may also exist between soy isoflavones and neurological agents, paying a potential role in Alzheimer’s disease (29).

Counseling Points

Dosing and Considerations

Osteoporosis: Doses of 80 mg of soy isoflavones daily for 12 months have been studied and are associated with reductions in bone resorption More significant improvements seen in women 4 years post-menopausal, lower body weight, and low calcium intake Menopause: 100 mg/day (up to 4 months); onset: may take > 3 months to see a 50% reduction in hot flushes (and possibly excessive sweating) To date, studies on the effect of soy isoflavone consumption on menopausal symptoms have reported mixed results Use products with higher amounts of genistein (≥15 mg) since supplements containing more genistein per treatment have shown greater reductions in hot flush symptoms Some health effects of soy isoflavones may be dependent on whether or not the isoflavone metabolite, equol, is produced in your body

Safety

Generally well tolerated Most common side effects are mild and include stomach upset and digestive problems (constipation, diarrhea) May reduce thyroid function , precipitate kidney stones, increased bleeding with antiplatelet drugs, hypotensive effect with antihypertensives, reduced effect with concurrent antibiotic administration Avoid soy isoflavone supplementation in pregnant and nursing mothers (estrogen-like effects) Food sources of soy isoflavones are likely safe in pregnancy and nursing when taken in standard dietary amounts (25-50 mg/day)

Product Recommendation

For osteoporosis prevention, we would order Maxilife Mega Soy 80 mg capsules. Each capsule is composed of Novasoy Purified Soy Extract (providing 40% isoflavones) which provides 80 mg of isoflavones including: 39 mg of genistein, 34 mg of daidzein and 7 mg of glycitein). At a dosage of 1 capsule per day, this is an ideal product since doses of 80 mg of soy isoflavones daily for 12 months have been studied and are associated with reductions in bone resorption. This product is also fairly cost effective; 1 bottle contains 60 capsules and currently retails for $22.38, meaning that each capsule only costs $0.37 and will last 60 days.

For menopausal symptom relief, we would order Natrol® Women's Soy Isoflavones capsules for our pharmacy. Each capsule contains 50 mg of total isoflavones (from soy extract) which is composed of 20 mg genistein, 17.5 mg daidzein, 6.25 mg glycitein, and 6.25 mg of other isoflavones. At a dosage of 2 capsules per day, this is an ideal product since 100 mg of soy isoflavones has been studied and shown to decrease the incidence of menopausal symptoms (hot flushes) in a majority of RCTs conducted. This preparation is favorable since soy isoflavone supplements containing a greater content of genistein (≥15 mg) per treatment reported a statistically significant decrease in hot flush symptoms compared to products containing less than 15 mg of genistein. Furthermore, 1 bottle contains 120 capsules and retails for $16.49, meaning that each capsule only costs $0.14, making it very cost efficient.

References

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  2. Ma D-F, Qin L-Q, Wang P-Y, Katoh R. Soy isoflavone intake inhibits bone resorption and stimulates bone formation in menopausal women: meta-analysis of randomized controlled trials. Eur J Clin Nutr. 2008 Feb;62(2):155–61.
  3. Cassidy A, Albertazzi P, Lise Nielsen I, Hall W, Williamson G, Tetens I, et al. Critical review of health effects of soyabean phyto-oestrogens in post-menopausal women. Proc Nutr Soc. 2006 Feb;65(1):76–92.
  4. Han KK, Soares JM Jr, Haidar MA, de Lima GR, Baracat EC. Benefits of soy isoflavone therapeutic regimen on menopausal symptoms. Obstet Gynecol. 2002 Mar;99(3):389–94.
  5. Faure ED, Chantre P, Mares P. Effects of a standardized soy extract on hot flushes: a multicenter, double-blind, randomized, placebo-controlled study. Menopause. 2002 Oct;9(5):329–34.
  6. Zittermann A, Geppert J, Baier S, Zehn N, Gouni-Berthold I, Berthold H, et al. Short-term effects of high soy supplementation on sex hormones, bone markers, and lipid parameters in young female adults. European Journal of Nutrition. 2004 Apr 1;43(2):100–8.
  7. Yamaguchi M. Regulatory mechanism of food factors in bone metabolism and prevention of osteoporosis. Yakugaku Zasshi. 2006 Nov;126(11):1117–37.
  8. Barnes S, Boersma B, Patel R, Kirk M, Darley-Usmar VM, Kim H, et al. Isoflavonoids and chronic disease: mechanisms of action. Biofactors. 2000;12(1-4):209–15.
  9. Akiyama T, Ishida J, Nakagawa S, Ogawara H, Watanabe S, Itoh N, et al. Genistein, a specific inhibitor of tyrosine-specific protein kinases. J. Biol. Chem. 1987 Apr 25;262(12):5592–5.
  10. Chiechi LM, Secreto G, D’Amore M, Fanelli M, Venturelli E, Cantatore F, et al. Efficacy of a soy rich diet in preventing postmenopausal osteoporosis: the Menfis randomized trial. Maturitas. 2002 Aug 30;42(4):295–300.
  11. Scheiber MD, Liu JH, Subbiah MT, Rebar RW, Setchell KD. Dietary inclusion of whole soy foods results in significant reductions in clinical risk factors for osteoporosis and cardiovascular disease in normal postmenopausal women. Menopause. 2001 Oct;8(5):384–92.
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  13. Harkness LS, Fiedler K, Sehgal AR, Oravec D, Lerner E. Decreased bone resorption with soy isoflavone supplementation in postmenopausal women. J Womens Health (Larchmt). 2004 Nov;13(9):1000–7.
  14. Wangen KE, Duncan AM, Merz-Demlow BE, Xu X, Marcus R, Phipps WR, et al. Effects of soy isoflavones on markers of bone turnover in premenopausal and postmenopausal women. J. Clin. Endocrinol. Metab. 2000 Sep;85(9):3043–8.
  15. Alekel DL, Germain AS, Peterson CT, Hanson KB, Stewart JW, Toda T. Isoflavone-rich soy protein isolate attenuates bone loss in the lumbar spine of perimenopausal women. Am. J. Clin. Nutr. 2000 Sep;72(3):844–52.
  16. Dalais FS, Rice GE, Wahlqvist ML, Grehan M, Murkies AL, Medley G, et al. Effects of dietary phytoestrogens in postmenopausal women. Climacteric. 1998 Jun;1(2):124–9.
  17. Cheong JMK, Martin BR, Jackson GS, Elmore D, McCabe GP, Nolan JR, et al. Soy isoflavones do not affect bone resorption in postmenopausal women: a dose-response study using a novel approach with 41Ca. J. Clin. Endocrinol. Metab. 2007 Feb;92(2):577–82.
  18. Potter SM, Baum JA, Teng H, Stillman RJ, Shay NF, Erdman JW Jr. Soy protein and isoflavones: their effects on blood lipids and bone density in postmenopausal women. Am. J. Clin. Nutr. 1998 Dec;68(6 Suppl):1375S–1379S.
  19. Kreijkamp-Kaspers S, Kok L, Grobbee DE, de Haan EHF, Aleman A, Lampe JW, et al. Effect of soy protein containing isoflavones on cognitive function, bone mineral density, and plasma lipids in postmenopausal women: a randomized controlled trial. JAMA. 2004 Jul 7;292(1):65–74.
  20. Lydeking-Olsen E, Beck-Jensen J-E, Setchell KDR, Holm-Jensen T. Soymilk or progesterone for prevention of bone loss–a 2 year randomized, placebo-controlled trial. Eur J Nutr. 2004 Aug;43(4):246–57.
  21. Chen Y-M, Ho SC, Lam SSH, Ho SSS, Woo JLF. Beneficial effect of soy isoflavones on bone mineral content was modified by years since menopause, body weight, and calcium intake: a double-blind, randomized, controlled trial. Menopause. 2004 Jun;11(3):246–54.
  22. Huang H-Y, Yang H-P, Yang H-T, Yang T-C, Shieh M-J, Huang S-Y. One-year soy isoflavone supplementation prevents early postmenopausal bone loss but without a dose-dependent effect. J. Nutr. Biochem. 2006 Aug;17(8):509–17.
  23. Nelson HD, Vesco KK, Haney E, Fu R, Nedrow A, Miller J, et al. Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis. JAMA. 2006 May 3;295(17):2057–71.
  24. Huntley AL, Ernst E. Soy for the treatment of perimenopausal symptoms—a systematic review. Maturitas. 2004 Jan 20;47(1):1–9.
  25. Howes LG, Howes JB, Knight DC. Isoflavone therapy for menopausal flushes: a systematic review and meta-analysis. Maturitas. 2006 Oct 20;55(3):203–11.
  26. Williamson-Hughes PS, Flickinger BD, Messina MJ, Empie MW. Isoflavone supplements containing predominantly genistein reduce hot flash symptoms: a critical review of published studies. Menopause. 2006 Oct;13(5):831–9.
  27. Jou H-J, Wu S-C, Chang F-W, Ling P-Y, Chu KS, Wu W-H. Effect of intestinal production of equol on menopausal symptoms in women treated with soy isoflavones. Int J Gynaecol Obstet. 2008 Jul;102(1):44–9.
  28. Bloedon LT, Jeffcoat AR, Lopaczynski W, Schell MJ, Black TM, Dix KJ, et al. Safety and pharmacokinetics of purified soy isoflavones: single-dose administration to postmenopausal women. Am. J. Clin. Nutr. 2002 Nov;76(5):1126–37.
  29. Isoflavones. In: Natural Standard: the authority on integrative medicine [database on the Internet]. Cambridge (MA): Natural Standard; 2008 [cited 26 March 2012]. Available from: http://www.naturalstandard.com.
  30. Isoda H, Talorete TPN, Kimura M, Maekawa T, Inamori Y, Nakajima N, et al. Phytoestrogens genistein and daidzin enhance the acetylcholinesterase activity of the rat pheochromocytoma cell line PC12 by binding to the estrogen receptor. Cytotechnology. 2002 Nov;40(1-3):117–23.
  31. Cheng S-Y, Shaw N-S, Tsai K-S, Chen C-Y. The hypoglycemic effects of soy isoflavones on postmenopausal women. J Womens Health (Larchmt). 2004 Dec;13(10):1080–6.

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