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 13th and 14th of May 2009 in Milan (Italy) under active participation of the EFSA (European Food Safety Authority).
Next to the debate on connections between isoflavones and breast cancer the BfR also postulates a risk at the endometrium (Anon. 2007). Again this is a hormone-sensitive tissue where estrogen is under suspicion of causing endometrial cancer. Estrogen therapy leads to an increase of endometrial thickness and to hyperplasia as a potential precursor of cancer (Furness et al. 2009). Prof. Mark Messina explained that such effects are unknown from epidemiological trials with soy preparations (Messina 2009) – in the contrary the data points to a protection against endometrial cancer by an increased intake of isoflavones (Goodman et al. 1997; Horn-Ross et al. 2003; Xu et al. 2004). In Asia the rate of endometrial carcinoma is approximately 12 times lower than in Eastern Europe. Whereas the world-wide incidence rate is at an average of 5.4 cancer cases per 100,000 women, the US-American average is 21.8, and the Chinese average 1.5 cases of endometrial carcinoma. This difference is not caused by genetic pre-disposition, as demonstrated in migrant studies. After emigration of Asians to countries with Western diet the incidence rate quickly follows the change in nutritional habits.
In the published literature Messina identified more than 20 studies with a duration of up to three years, and daily doses of 35-132 mg of isoflavones (Albertazzi et al. 2005; Baber et al. 1999; Balk et al. 2002; Burke et al. 2003; Caserta et al. 2005; Cheng et al. 2007; Crisafulli et al. 2004; D'Anna et al. 2007; Duncan et al. 1999b; Duncan et al. 1999a; Han et al. 2002; Kaari et al. 2006; Marini et al. 2008; Nahas et al. 2007; Nikander et al. 2005; Penotti et al. 2003; Petri Nahas et al. 2004; Powles et al. 2008; Sammartino et al. 2003; Scambia et al. 2000; Upmalis et al. 2000). In no case this intake had an effect on the structure of the endometrium. In one of these studies a growth of the endometrial mucosa was observed in postmenopausal women under the influence of estradiol. Additional intake of 120 mg of isoflavones did by no means increase this growth – as would be expected from the BfR’s hypothesis (Anon. 2007) –, but in the contrary reduced the growth, although the effect was not statistically significant (Murray et al. 2003).
In at least nine of the studies examining the endometrium biopsies were taken. Eight of the studies did not show an effect of isoflavones on the mucosa. One Italian study (Unfer et al. 2004) is still the only clinical contribution potentially pointing to clinical changes of the uterine mucosa after intake of highly doses isoflavones (150 mg) for 5 years. Through biopsies hyperplasia of the endometrium was observed in 6 women (3.7 %) of the verum group after five years, whereas none was observed in the placebo group (Unfer et al. 2004).
For various reasons this study has been questioned by experts in gynaecology (Messina 2008). The most essential reason was that at the start of the study the histological samples were unassessable in every fourth woman (approximately 25 %), but the women were still enrolled in the trial. In addition, one quarter of the biopsies in both groups was not assessable at the end of the study – but the authors do not mention whether for the women where hyperplasia was found there were in fact the corresponding pre/post pairs of data. It can therefore not be excluded that hyperplasia was already present at the start of the study.
The most essential criticism of Prof. Messina regarding this study was, however, the lack of observation of a single case of hyperplasia in the placebo group. A 3-year study in postmenopausal women had demonstrated an incidence rate of 2.4 % of cases of endometrial hyperplasia in the placebo group (Legault et al. 1998). After five study years cases would therefore necessarily have to be expected. The fact that Unfer et al. (2004) did not observe a single case of hyperplasia in the placebo group must be considered a medicinal anomaly. Already one single case would, however, have caused a loss of statistical significance in the intergroup comparison.
The lack of negative effects respectively the existence of a protective effect at the endometrium has been described for soy in two epidemiological studies in 1,154 pre- and postmenopausal women and 1,357 case controls (Goodman et al. 1997; Xu et al. 2004). In both studies there was a reduced risk of endometrial cancer with an increase of isoflavone intake. All taken together there is no recognizable risk. In the contrary the data speak in favour of a protection of the endometrium. Messina therefore said he was lacking an understandable basis to disrecommend the use of soy products in women with a potential endometrial risk.
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
Anon. (2007). Isolierte Isoflavone in Nahrungsergänzungsmitteln und bilanzierten Diäten. Gesundheitliche Bewertung des BfR vom 30 11 2007.
Albertazzi P, Steel SA and Bottazzi M (2005). Effect of pure genistein on bone markers and hot flushes. Climacteric 8(4):371-379.
Baber RJ, Templeman C, Morton T, Kelly GE and West L (1999). Randomized placebo-controlled trial of an isoflavone supplement and menopausal symptoms in women. Climacteric 2(2):85-92.
Balk JL, Whiteside DA, Naus G, DeFerrari E and Roberts JM (2002). A pilot study of the effects of phytoestrogen supplementation on postmenopausal endometrium. J Soc Gynecol Investig 9(4):238-242.
Burke GL, Legault C, Anthony M, Bland DR, Morgan TM, Naughton MJ, Leggett K, Washburn SA and Vitolins MZ (2003). Soy protein and isoflavone effects on vasomotor symptoms in peri- and postmenopausal women: the Soy Estrogen Alternative Study. Menopause 10(2):147-153.
Caserta L, Caserta R, Torella M, Nappo C, De Lucia D and Panariello S (2005). Effetti della terapia con fitoestrogeni sulla mucosa endometriale in postmenopausa. Minerva Ginecol 57(5):551-555.
Cheng G, Wilczek B, Warner M, Gustafsson JA and Landgren BM (2007). Isoflavone treatment for acute menopausal symptoms. Menopause 14(3 Pt 1):468-473.
Crisafulli A, Marini H, Bitto A, Altavilla D, Squadrito G, Romeo A, Adamo EB, Marini R, D'Anna R, Corrado F, Bartolone S, Frisina N and Squadrito F (2004). Effects of genistein on hot flushes in early postmenopausal women: a randomized, double-blind EPT- and placebo-controlled study. Menopause 11(4):400-404.
D'Anna R, Cannata ML, Atteritano M, Cancellieri F, Corrado F, Baviera G, Triolo O, Antico F, Gaudio A, Frisina N, Bitto A, Polito F, Minutoli L, Altavilla D, Marini H and Squadrito F (2007). Effects of the phytoestrogen genistein on hot flushes, endometrium, and vaginal epithelium in postmenopausal women: a 1-year randomized, double-blind, placebo-controlled study. Menopause 14(4):648-655.
Duncan AM, Merz BE, Xu X, Nagel TC, Phipps WR and Kurzer MS (1999a). Soy isoflavones exert modest hormonal effects in premenopausal women. J Clin Endocrinol Metab 84(1):192-197.
Duncan AM, Underhill KE, Xu X, Lavalleur J, Phipps WR and Kurzer MS (1999b). Modest hormonal effects of soy isoflavones in postmenopausal women. J Clin Endocrinol Metab 84(10):3479-3484.
Furness S, Roberts H, Marjoribanks J, Lethaby A, Hickey M and Farquhar C (2009). Hormone therapy in postmenopausal women and risk of endometrial hyperplasia. Cochrane Database Syst Rev(2):CD000402.
Goodman MT, Wilkens LR, Hankin JH, Lyu LC, Wu AH and Kolonel LN (1997). Association of soy and fiber consumption with the risk of endometrial cancer. Am J Epidemiol 146(4):294-306.
Han KK, Soares JM, Jr., Haidar MA, de Lima GR and Baracat EC (2002). Benefits of soy isoflavone therapeutic regimen on menopausal symptoms. Obstet Gynecol 99(3):389-394.
Horn-Ross PL, John EM, Canchola AJ, Stewart SL and Lee MM (2003). Phytoestrogen intake and endometrial cancer risk. J Natl Cancer Inst 95(15):1158-1164.
Kaari C, Haidar MA, Junior JM, Nunes MG, Quadros LG, Kemp C, Stavale JN and Baracat EC (2006). Randomized clinical trial comparing conjugated equine estrogens and isoflavones in postmenopausal women: a pilot study. Maturitas 53(1):49-58.
Legault C, Espeland MA, Wasilauskas CH, Bush TL, Trabal J, Judd HL, Johnson SR and Greendale GA (1998). Agreement in assessing endometrial pathology: the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. J Womens Health 7(4):435-442.
Marini H, Bitto A, Altavilla D, Burnett BP, Polito F, Di Stefano, V, Minutoli L, Atteritano M, Levy RM, D'Anna R, Frisina N, Mazzaferro S, Cancellieri F, Cannata ML, Corrado F, Frisina A, Adamo V, Lubrano C, Sansotta C, Marini R, Adamo EB and Squadrito F (2008). Breast Safety and efficacy of genistein aglycone for post-menopausal bone loss: A follow-up study. J Clin Endocrinol Metab 93(12):7487-7496.
Messina M (2008). The endometrial effects of isoflavones: a discussion paper. Complement Ther Clin Pract 14(3):212-214.
Messina M (2009). Effects of isoflavones on endometrial tissue and endometrial cancer risk. Symposium on Evaluating the Efficacy and Safety of Isoflavones for Postmenopausal Women, 13-14 May. Milan (Italy): Council for Responsible Nutrition.
Murray MJ, Meyer WR, Lessey BA, Oi RH, DeWire RE and Fritz MA (2003). Soy protein isolate with isoflavones does not prevent estradiol-induced endometrial hyperplasia in postmenopausal women: a pilot trial. Menopause 10(5):456-464.
Nahas EAP, Nahas-Neto J, Orsatti FL, Carvalho EP, Oliveira ML and Dias R (2007). Efficacy and safety of a soy isoflavone extract in postmenopausal women: A randomized, double-blind, and placebo-controlled study. Maturitas 58(3):249-258.
Nikander E, Rutanen EM, Nieminen P, Wahlstrom T, Ylikorkala O and Tiitinen A (2005). Lack of effect of isoflavonoids on the vagina and endometrium in postmenopausal women. Fertil Steril 83(1):137-142.
Penotti M, Fabio E, Modena AB, Rinaldi M, Omodei U and Vigano P (2003). Effect of soy-derived isoflavones on hot flushes, endometrial thickness, and the pulsatility index of the uterine and cerebral arteries. Fertil Steril 79(5):1112-1117.
Petri Nahas EA, Nahas Neto J, De Luca L, Traiman P, Pontes A and Dalben I (2004). Benefits of soy germ isoflavones in postmenopausal women with contraindication for conventional hormone replacement therapy. Maturitas 48(4):372-380.
Powles TJ, Howell A, Evans DG, McCloskey EV, Ashley S, Greenhalgh R, Affen J, Flook LA and Tidy A (2008). Red clover isoflavones are safe and well tolerated in women with a family history of breast cancer. Menopause Int 14(1):6-12.
Sammartino A, Di Carlo C, Mandato VD, Bifulco G, Di Stefano M and Nappi C (2003). Effects of genistein on the endometrium: ultrasonographic evaluation. Gynecol Endocrinol 17(1):45-49.
Scambia G, Mango D, Signorile PG, Anselmi Angeli RA, Palena C, Gallo D, Bombardelli E, Morazzoni P, Riva A and Mancuso S (2000). Clinical effects of a standardized soy extract in postmenopausal women: a pilot study. Menopause 7(2):105-111.
Unfer V, Casini ML, Costabile L, Mignosa M, Gerli S and Di Renzo GC (2004). Endometrial effects of long-term treatment with phytoestrogens: a randomized, double-blind, placebo-controlled study. Fertil Steril 82(1):145-148.
Upmalis DH, Lobo R, Bradley L, Warren M, Cone FL and Lamia CA (2000). Vasomotor symptom relief by soy isoflavone extract tablets in postmenopausal women: a multicenter, double-blind, randomized, placebo-controlled study. Menopause 7(4):236-242.
Xu WH, Zheng W, Xiang YB, Ruan ZX, Cheng JR, Dai Q, Gao YT and Shu XO (2004). Soya food intake and risk of endometrial cancer among Chinese women in Shanghai: population based case-control study. BMJ 328(7451):1285.
Safety 