Isoflavone Research Initiative

The safety of application and the benefits of isoflavones for postmenopausal women were the focus of a symposium organised by the CRN (Council for Responsible Nutrition), which took place on the 13^th and 14^th of May 2009 in Milan (Italy) under active participation of the EFSA (European Food Safety Authority).

The hypothesis of soy-induced risks in the sense of cancer inducing effects in hormone-sensitive tissue is based on the equation of “phyto-estrogens” with the hormone estrogen. After the publication of the Women’s Health Initiative, also known as WHI study, the connection between estrogen therapy and breast cancer seemed secured in menopausal women (Rossouw et al. 2002). Consequently and logically taken one step further is appears clear: if estrogen can cause cancer in menopause this should also apply to phyto-estrogens – of course provided the phyto-estrogens act exactly like estrogens in the organism – which is, however, not the case. But even the seemingly secured knowledge of cancer stimulation through estrogen was presented in a different context in a subsequent re-evaluation of the WHI study, and was disproved under defined conditions. Accordingly, it is not estrogen alone, but the combination with synthetic progesterone derivatives, the gestagens, which is responsible for the stimulation of breast cancer (Conner et al. 2008). This, however, pulls the rug out from under the hypothesis estrogen = phyto-estrogen = breast cancer: If estrogens are not responsible for the induction of breast cancer, phyto-estrogens as estrogen-analogous substances would likewise not cause the effect.

The presentation of Prof. Gunnar Søderqvist of the Swedish Karolinska institute was dedicated to this controversy (Söderqvist 2009). He spoke of the effects of hormone therapy on breast tissue density and cell proliferation (Hofseth et al. 1999; Lundström et al. 2002). Breast tissue is a marker for breast cancer risk (Boyd et al. 2009; Cummings et al. 2009). In studies involving more than 600 women the working group of Søderqvist examined the influence of various hormone therapies on breast tissue density (Conner et al. 2001; Conner et al. 2003; Conner et al. 2004a; Conner et al. 2004b; Conner et al. 2008; Isaksson et al. 2001; Lundström et al. 1999; Lundström et al. 2002; Söderqvist et al. 2004). They found an increase of breast tissue density and cell proliferation only in women treated with high combined doses of estrogen and gestagen (2 mg estradiol + 1 mg norethisteron acetate). In contrast, estradiol as an intravaginal gel as well as dermal estradiol (1.5 mg) combined with orally applied bioidentical progesterone did not have an impact on breast tissue density.

Consequently, there is in fact a potential of estrogen for breast cancer stimulation, but only in high doses, and eventually only when combined with gestagens (Conner et al. 2008). A negative impact of isoflavones in the sense of triggering breast cancer would therefore not even be expected if isoflavones mediated their effect exclusively through the proliferation-enhancing receptor ER-α. Isoflavones do, however, preferentially act through ER-β, a receptor system which is made responsible for protective effects against hormone-induced cell division (McCarty 2006).

Further reports from the Milan 2009 Soy Safety Symposium:

1. Plant “hormones”: Guilty by association with estrogens? International Symposium in Milan on the safety and efficacy of soy

2. Facts Related to Bioavailability

3. Lack of relevance of animal models for an extrapolation of risks of isoflavones

4. Isoflavones protect „menopausal” mice from breast cancer

5. Breast cancer risk is increased by synthetic gestagens

6. Breast tissue density remains unaltered with soy

7. Clinical studies demonstrate safety of soy in the breast

8. Study in more than 5,000 breast cancer patients: First positive tendencies with soy!

9. No effects of isoflavones on the endometrium

10. Isoflavones also safe at the thyroid gland

11. Backgrounds on Menopausal Hot Flushes

12. Clinical safety of isoflavone-containing preparations

13. Clinical effects of isoflavones against menopausal hot flushes

References

Boyd NF, Martin LJ, Rommens JM, Paterson AD, Minkin S, Yaffe MJ, Stone J and Hopper JL (2009). Mammographic density: a heritable risk factor for breast cancer. Methods Mol Biol 472:343-360.

Conner P, Christow A, Kersemaekers W, Soderqvist G, Skoog L, Carlstrom K, Tani E, Mol-Arts M and von Schoultz B (2004a). A comparative study of breast cell proliferation during hormone replacement therapy: effects of tibolon and continuous combined estrogen-progestogen treatment. Climacteric 7(1):50-58.

Conner P, Lundström E and von Schoultz B (2008). Breast cancer and hormonal therapy. Clin Obstet Gynecol 51(3):592-606.

Conner P, Skoog L and Söderqvist G (2001). Breast epithelial proliferation in postmenopausal women evaluated through fine-needle-aspiration cytology. Climacteric 4(1):7-12.

Conner P, Söderqvist G, Skoog L, Graser T, Walter F, Tani E, Carlstrom K and von Schoultz B (2003). Breast cell proliferation in postmenopausal women during HRT evaluated through fine needle aspiration cytology. Breast Cancer Res Treat 78(2):159-165.

Conner P, Svane G, Azavedo E, Soderqvist G, Carlstrom K, Graser T, Walter F and von Schoultz B (2004b). Mammographic breast density, hormones, and growth factors during continuous combined hormone therapy. Fertil Steril 81(6):1617-1623.

Cummings SR, Tice JA, Bauer S, Browner WS, Cuzick J, Ziv E, Vogel V, Shepherd J, Vachon C, Smith-Bindman R and Kerlikowske K (2009). Prevention of breast cancer in postmenopausal women: approaches to estimating and reducing risk. J Natl Cancer Inst 101(6):384-398.

Hofseth LJ, Raafat AM, Osuch JR, Pathak DR, Slomski CA and Haslam SZ (1999). Hormone replacement therapy with estrogen or estrogen plus medroxyprogesterone acetate is associated with increased epithelial proliferation in the normal postmenopausal breast. J Clin Endocrinol Metab 84(12):4559-4565.

Isaksson E, von Schoultz E, Odlind V, Soderqvist G, Csemiczky G, Carlstrom K, Skoog L and von Schoultz B (2001). Effects of oral contraceptives on breast epithelial proliferation. Breast Cancer Res Treat 65(2):163-169.

Lundström E, Christow A, Kersemaekers W, Svane G, Azavedo E, Soderqvist G, Mol-Arts M, Barkfeldt J and von Schoultz B (2002). Effects of tibolone and continuous combined hormone replacement therapy on mammographic breast density. Am J Obstet Gynecol 186(4):717-722.

Lundström E, Wilczek B, von Palffy Z, Söderqvist G and von Schoultz B (1999). Mammographic breast density during hormone replacement therapy: differences according to treatment. Am J Obstet Gynecol 181(2):348-352.

McCarty MF (2006). Isoflavones made simple - Genistein's agonist activity for the beta-type estrogen receptor mediates their health benefits. Med Hypotheses 66(6):1093-1114.

Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM and Ockene J (2002). Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 288(3):321-333.

Söderqvist G (2009). Effects of conventional hormone therapy (HT) on breast tissue density and cell proliferation. Symposium on Evaluating the Efficacy and Safety of Isoflavones for Postmenopausal Women, 13-14 May. Milan (Italy): Council for Responsible Nutrition.

Söderqvist G and von Schoultz B (2004). Lessons to be learned from clinical studies on hormones and the breast. Maturitas 49(1):90-96.