Phytoestrogens for menopausal vasomotor symptoms

Anne Lethaby, Jane Marjoribanks, Fredi Kronenberg, Helen Roberts, John Eden, Julie Brown, Anne Lethaby, Jane Marjoribanks, Fredi Kronenberg, Helen Roberts, John Eden, Julie Brown

Abstract

Background: Vasomotor symptoms, such as hot flushes and night sweats, are very common during the menopausal transition. Hormone therapy has traditionally been used as a highly effective treatment, but concerns about increased risk of some chronic diseases have markedly increased the interest of women in alternative treatments. Some of the most popular of these treatments are foods or supplements enriched with phytoestrogens-plant-derived chemicals that have estrogenic action.

Objectives: To assess the efficacy, safety and acceptability of food products, extracts and dietary supplements containing high levels of phytoestrogens when compared with no treatment, placebo or hormone therapy for the amelioration of vasomotor menopausal symptoms (such as hot flushes and night sweats) in perimenopausal and postmenopausal women.

Search methods: Searches targeted the following electronic databases: the Cochrane Menstrual Disorders and Subfertility Group Specialised Register of randomised trials (29 July 2013), the Cochrane Register of Controlled Trials (CENTRAL; 29 July 2013), MEDLINE (inception to 29 July 2013), EMBASE (inception to 29 July 2013), AMED (1985 to 29 July 2013), PsycINFO (inception to 29 July 2013) and CINAHL (inception to 29 July 2013). Attempts were made to access grey literature by sending letters to pharmaceutical companies and performing searches of ongoing trial registers. Reference lists of included trials were also searched.

Selection criteria: Studies were included if they were randomised, included perimenopausal or postmenopausal participants with vasomotor symptoms (hot flushes or night sweats), lasted at least 12 weeks and provided interventions such as foods or supplements with high levels of phytoestrogens (not combined with other herbal treatments). Trials that included women who had breast cancer or a history of breast cancer were excluded.

Data collection and analysis: Selection of trials, extraction of data and assessment of quality were undertaken by at least two review authors. Most trials were too dissimilar for their results to be combined in a meta-analysis, so these findings are provided in narrative 'Summary of results' tables. Studies were grouped into broad categories: dietary soy, soy extracts, red clover extracts, genistein extracts and other types of phytoestrogens. Five trials used Promensil, a red clover extract; results of these trials were combined in a meta-analysis, and summary effect measures were calculated.

Main results: A total of 43 randomised controlled trials (4,364 participants) were included in this review. Very few trials provided data suitable for inclusion in a meta-analysis. Among the five trials that yielded data assessing the daily frequency of hot flushes suitable for pooling, no significant difference overall was noted in the incidence of hot flushes between participants taking Promensil (a red clover extract) and those given placebo (mean difference (MD) -0.93, 95% confidence interval (CI) -1.95 to 0.10, I(2) = 31%). No evidence indicated a difference in percentage reduction in hot flushes in two trials between Promensil and placebo (MD 20.15, 95% CI -12.08 to 52.38, I(2) = 82%). Four trials that were not combined in meta-analyses suggested that extracts with high (> 30 mg/d) levels of genistein consistently reduced the frequency of hot flushes. Individual results from the remaining trials were compared in broad subgroups such as dietary soy, soy extracts and other types of phytoestrogens that could not be combined. Some of these trials found that phytoestrogen treatments alleviated the frequency and severity of hot flushes and night sweats when compared with placebo, but many trials were small and were determined to be at high risk of bias. A strong placebo effect was noted in most trials, with a reduction in frequency ranging from 1% to 59% with placebo. No indication suggested that discrepant results were due to the amount of isoflavone in the active treatment arm, the severity of vasomotor symptoms or trial quality factors. Also, no evidence indicated that these treatments caused oestrogenic stimulation of the endometrium or the vagina or other adverse effects when used for up to two years.

Authors' conclusions: No conclusive evidence shows that phytoestrogen supplements effectively reduce the frequency or severity of hot flushes and night sweats in perimenopausal or postmenopausal women, although benefits derived from concentrates of genistein should be further investigated.

Conflict of interest statement

Anne Lethaby provided advice and suggestions to the author of the unpublished Brazilian study (Bicca 2004) that has been included in this review. She is included as an author of that unpublished paper.

John Eden is an author of two of the included studies (Knight 1999; Knight 2001).

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
Forest plot of comparison: 1 Promensil versus placebo, outcome: 1.1 Incidence of hot flushes (number/d).
1.1. Analysis
1.1. Analysis
Comparison 1 Promensil versus placebo, Outcome 1 Incidence of hot flushes (number/d).
1.2. Analysis
1.2. Analysis
Comparison 1 Promensil versus placebo, Outcome 2 Change in frequency of hot flushes (% reduction).
1.3. Analysis
1.3. Analysis
Comparison 1 Promensil versus placebo, Outcome 3 Improvement in hot flush severity rate.
1.4. Analysis
1.4. Analysis
Comparison 1 Promensil versus placebo, Outcome 4 Change in vasomotor score from baseline to end of study/vasomotor severity—Kupperman subscale.
1.5. Analysis
1.5. Analysis
Comparison 1 Promensil versus placebo, Outcome 5 Endometrial thickness (mm) after treatment.
1.6. Analysis
1.6. Analysis
Comparison 1 Promensil versus placebo, Outcome 6 Adverse event rates.
1.7. Analysis
1.7. Analysis
Comparison 1 Promensil versus placebo, Outcome 7 Incidence of specific adverse events.

References

References to studies included in this review Albertazzi 1998 {published data only}

    1. Albertazzi P, Pansini F, Bonaccorsi G, Zanotti L, Forini E, Aloysio D. The effect of dietary soy supplementation on hot flushes. Obstetrics and Gynecology 1998;91:6‐11.
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Aso 2012 {published data only}
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Baber 1999 {published data only}
    1. Baber RJ, Templeman C, Morton T, Kelly GE, West L. Randomized placebo‐controlled trial of an isoflavone supplement and menopausal symptoms in women. Climacteric 1999;2:85‐92.
Balk 2002 {published data only}
    1. Balk JL, Whiteside DA, Naus G, DeFerrari E, Roberts JM. A pilot study of the effects of phytoestrogen supplementation on the postmenopausal endometrium. Journal of the Society for Gynecologic Investigation 2002;9:238‐42.
Bicca 2004 {unpublished data only}
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Burke 2003 {published data only}
    1. Burke GL, Legault C, Anthony M, Bland DR, Morgan TM, Naughton MJ, et al. Soy protein and isoflavone effects on vasomotor symptoms in peri‐ and postmenopausal women: the Soy Estrogen Alternative Study. Menopause 2003;10(2):147‐53.
Campagnoli 2005 {published data only}
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Carmigiani 2010 {published data only}
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Cheng 2007 {published data only}
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Colli 2012 {published data only}
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Crisafulli 2004 {published data only}
    1. Crisafulli A, Marini H, Bitto A, Altavilla D, Squadrito G, Romeo A, et al. Effects of genistein on hot flushes in early postmenopausal women: a randomized, double‐blind EPT‐ and placebo‐ controlled study. Menopause 2004;11:400‐4.
D'Anna 2007 {published data only}
    1. D'Anna R, Cannata M, Atteritano M, Cancellieri F, Corrado F, Baviera G, et al. 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 2007;14(4):648‐55.
    1. D'Anna R, Cannata ML, Marini H, Atteritano M, Cancellieri F, Corrado F, et al. Effects of the phytoestrogen genistein on hot flushes, endometrium and vaginal epithelium in postmenopausal women: a 2‐year randomised, double‐blind, placebo‐controlled study. Menopause 2009;16(2):301‐6.
Dalais 1998 {published data only}
    1. Dalais FS, Rice GE, Wahlqvist ML, Grehan M, Murkies AL, Medley G, et al. Effects of dietary phytoestrogens in postmenopausal women. Climacteric 1998;1:124‐9.
Del Giorno 2010 {published data only}
    1. Giorno C, Maggio da Fonseca A, Bagnoli VR, Serrano de Assis J, Soares JM, Baracat EC. Effects of trifolium pratense on climacteric and sexual symptoms in postmenopausal women. Revista da Associacao Medica Brasileira 2010;56(5):558‐62.
Evans 2011 {published data only}
    1. Evans M, Ellito JG, Sharma P, Berman R, Guthrie N. The effect of synthetic genistein on menopause symptom management in healthy postmenopausal women: a multi‐center, randomised, placebo‐controlled study. Maturitas 2011;68:189‐96.
Faure 2002 {published data only}
    1. Faure ED, Chantre P, Mares P. Effects of a standardised soy extract on hot flushes: a multicentre, double‐blind, randomised placebo‐controlled study. Menopause 2002;9(5):329‐34.
Ferrari 2009 {published data only}
    1. Ferrari A. Soy extract phytoestrogens with high dose of isoflavones for menopausal symptoms. Journal of Obstetric and Gynaecological Research 2009;35(6):1083‐90.
Geller 2009 {published data only}
    1. Geller SE, Shulman LP, Breemen RB, Banuvar S, Zhou Y, Epstein G, et al. Safety and efficacy of black cohosh and red clover for the management of vasomotor symptoms: a randomised controlled trial. Menopause 2009;16(6):1156‐66.
Han 2002 {published data only}
    1. Han KK, Soares JM, Haidar MA, Lima GR, Baracat EC. Benefits of soy isoflavone therapeutic regimen on menopausal symptoms. Obstetrics and Gynecology 2002;99:389‐94.
Hanachi 2008 {published data only}
    1. Hanachi P, Golkho S. Assessment of soy phytoestrogens and exercise on lipid profiles and menopause symptoms in menopausal women. Journal of Biological Sciences 2008;8(4):789‐93.
Heger 2006 {published data only}
    1. Heger M, Ventskovskiy BM, Borzenko I, Kneis KC, Rettenberger R, Kaszkin‐Bettag M, et al. Efficacy and safety of a special extract of Rheum rhaponticum (ERr 731) in perimenopausal women with climacteric complaints: a 12‐week randomised double‐blind placebo‐controlled trial. Menopause 2006;13(5):744‐59.
Heyerick 2006 {published data only}
    1. Heyerick A, Vervarcke S, Depypere H, Bracke M, Keukeleire D. A first prospective, randomized, double‐blind, placebo‐controlled study on the use of a standardized hop extract to alleviate menopausal discomforts. Maturitas 2006;54:164‐75.
Hidalgo 2005 {published data only}
    1. Hidalgo LA, Chedraui PA, Morocho N, Ross S, San Miguel G. The effect of red clover isoflavones on menopausal symptoms, lipids and vaginal cytology in menopausal women: a randomized, double‐blind, placebo‐controlled study. Gynecological Endocrinology 2005;21(5):257‐64.
Imhof 2006 {published data only}
    1. Imhof M, Gocan A, Reithmayer F, Lipovac M, Schimitzek C, Chedraui P, et al. Effects of a red clover extract (MF11RCE) on endometrium and sex hormones in postmenopausal women. Maturitas 2006;55:76‐81.
    1. Lipovac M, Chedraui P, Gruenhut C, Gocan A, Kurz C, Neuber B, et al. The effect of red clover isoflavone supplementation over vasomotor and menopausal symptoms in postmenopausal women. Gynecological Endocrinology 2012;28(3):203‐7.
Jeri 2002 {published data only}
    1. Jeri A. The use of an isoflavone supplement to relieve hot flushes. The Female Patient 2002;27:47‐9.
Jou 2008 {published data only}
    1. 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. International Journal of Gynecology and Obstetrics 2008;102:44‐9.
Kaari 2006 {published data only}
    1. Kaari C, Haidar MA, Soares Junior JM, Nunes MG, Azevedo Quadros LG, Kemp C, et al. Randomized clinical trial comparing conjugated equine estrogens and isoflavones in postmenopausal women: a pilot study. Maturitas 2006;53:49‐58.
Khaodhiar 2008 {published data only}
    1. Khaodhiar L, Ricciotti HA, Li L, Pan W, Schickel M, Zhou J, et al. Daidzein‐rich isoflavone‐aglycones are effective in reducing hot flashes in menopausal women. Menopause 2008;15(1):125‐32.
Knight 1999 {published data only}
    1. Knight DC, Howes JB, Eden JA. The effect of Promensil, an isoflavone extract, on menopausal symptoms. Climacteric 1999;2:79‐84.
Knight 2001 {published data only}
    1. Knight DC, Howes JB, Eden JA, Howes LG. Effects on menopausal symptoms and acceptability of isoflavone‐containing soy powder dietary supplementation. Climacteric 2001;4:13‐8.
Kotsopoulos 2000 {published data only}
    1. Kotsopoulos D, Dalais FS, Liang Y‐L, McGrath BP, Teede HJ. The effects of soy protein containing phytoestrogens on menopausal symptoms in postmenopausal women. Climacteric 2000;3:161‐7.
Levis 2011 {published data only}
    1. Levis S, Strickman‐Stein N, Ganjei‐Azar P, Xu P, Doerge D, Krischer J. Soy isoflavones in the prevention of menopausal bone loss and menopausal symptoms. Archives of Internal Medicine 2011;171(15):1363‐8.
Lewis 2006 {published data only}
    1. Lewis JE, Nickell LA, Thompson LU, Szalai JP, Kiss A, Hilditch JR. A randomized controlled trial of the effect of dietary soy and flaxseed muffins on quality of life and hot flashes during menopause. Menopause 2006;13(4):631‐42.
Nahas 2007 {published data only}
    1. Nahas E, Nahas‐Neto J, Orsatti F, Carvalho E, Oliveira M, Dias R. Efficacy and safety of a soy isoflavone extract in postmenopausal women: a randomized double‐blind, and placebo controlled study. Maturitas 2007;58:249‐58.
Penotti 2003 {published data only}
    1. Penotti M, Fabio E, Modena AB, Rinaldi M, Omodei U, Vigano P. Effect of soy‐derived isoflavones on hot flushes, endometrial thickness and the pulsatility index of the uterine and cerebral arteries. Fertility and Sterility 2003;79(5):1112‐7.
    1. Penotti M, Fabio E, Rinaldi M, Omodei U, Bacchi M. Effects of soy‐derived isoflavones on hot flushes and vascular reactivity. The 10th World Congress on the Menopause, Berlin, Germany. 10‐14 June 2002:Abstract F‐27‐01.
Radhakrishnan 2009 {published data only}
    1. Radhakrishnan G, Agarwal N, Vaid N. Evaluation of isoflavone rich soy protein supplementation for postmenopausal therapy. Pakistan Journal of Nutrition 2009;8(7):1009‐17.
Sammartino 2003 {published data only}
    1. Sammartino A, Carlo C, Mandato VD, Bifulco G, Stefano M, Nappi C. Effects of genistein on the endometrium: ultrasonographic evaluation. Gynecological Endocrinology 2003;17(1):45‐9.
St Germain 2001 {published data only}
    1. Germain A, Peterson CT, Robinson JG, Alekel DL. Isoflavone‐rich or isoflavone‐poor soy protein does not reduce menopausal symptoms during 24 weeks of treatment. Menopause 2002;8(1):17‐26.
Tice 2003 {published data only}
    1. Tice JA, Ettinger B, Ensrud K, Wallace R, Blackwell T, Cummings SR. Phytoestrogen supplements for the treatment of hot flashes: the isoflavone clover extract (ICE) study. JAMA 2003;290(2):207‐14.
Upmalis 2000 {published data only}
    1. Upmalis DH, Lobo R, Bradley L, Warren M, Cone FL, Lamia CA. Vasomotor symptom relief by soy isoflavone extract tablets in postmenopausal women: a multicenter double‐blind randomized placebo‐controlled study. Menopause 2000;7(4):236‐42.
van de Weijer 2002 {published data only}
    1. Weijer PHM, Barentsen R. Isoflavones from red clover (Promensil) significantly reduce menopausal hot flush symptoms compared with placebo. Maturitas 2002;42:187‐93.
Ye 2012 {published data only}
    1. Ye Y‐B, Wang Z‐L, Zhuo S‐Y, Lu W, Liao H‐F, Verbruggen MA, et al. Soy germ isoflavones improve menopausal symptoms but have no effect on blood lipids in early postmenopausal Chinese women: a randomised placebo‐controlled trial. Menopause 2012;19(7):791‐8.
References to studies excluded from this review Albert 2001 {published data only}
    1. Albert A, Altabre C, Baro F, Cabero A, Cancelo MJ, Castelo‐Branco C, et al. Assessment of the efficiency and safety of soya‐extracted phytoestrogens (Glycine Max L), in the treatment of climacteric symptoms. Results of a mulicenter, open, prospective pilot study [Valoracion de la eficacia y seguridad de una preparacion de fitoestrogenos extraidos de la soja (Glycine Max L.) en al tratamiento de la sintomatologia climaterica. Resultados de un ensayo piloto multicentrico, abierto y prospectivo]. Toko‐ginecologia Practica 2001;60(5):257‐64.
Albertazzi 2005 {published data only}
    1. Albertazzi P, Steel SA, Bottazzi M. Effect of pure genistein on bone markers and hot flushes. Climacteric 2005;8(4):371‐9.
Aly 2009 {published data only}
    1. Aly M. Use of black cohosh (Cimicifuga racemosa) in postmenopausal women: a randomized controlled study. International Journal of Gynecology & Obstetrics 2009;107(Suppl 2):S413‐729.
Amato 2005 {published data only}
    1. Amato P, Young R, Cramer M, Lewis R, Murray M, Steinberg F, et al. The effect of soy isoflavone supplementation on menopausal quality of life: a multicenter, randomised controlled trial. 16th Annual Meeting of NAMS, San Diego, CA, USA. September‐October 2005.
    1. Amato P, Young RL, Steinberg FM, Murray MJ, Lewis RD, Cramer MA, et al. Effect of soy isoflavone supplementation on menopausal quality of life. Menopause 2013;20(4):443‐7.
Atkinson 2003 {published data only}
    1. Atkinson C, Warren RML, Sala E, Dowsett M, Dunning AM, Healey CS, et al. Red clover‐derived isoflavones and mammographic breast density: a double‐blind, randomized, placebo‐controlled trial. Breast Cancer Research 2004;6(3):R170‐9.
Bai 2007 {published data only}
    1. Bai W, Henneicke‐von Zepelin H‐H, Wang S, Zheng S, Liu J, Zhang Z, et al. Efficacy and tolerability of a medicinal product containing isopropanolic black cohosh extract in Chinese women with menopausal symptoms: a randomized, double blind, parallel‐controlled study versus tibolone. Maturitas 2007;58:31‐41.
Baird 1995 {published data only}
    1. Baird DB, Umbach DM, Lansdell L, Hughes CL, Setchell KDR, Weinberg CR, et al. Dietary intervention study to assess estrogenicity of dietary soy among postmenopausal women. Journal of Clinical Endocrinology and Metabolism 1995;80(5):1685‐90.
Cancellieri 2007 {published data only}
    1. Cancellieri F, Leo V, Genazzani AD, Nappi C, Parenti GL, Polatti F, et al. Efficacy on menopausal neurovegetative symptoms and some plasma lipids blood levels of an herbal product containing isoflavones and other plant extracts. Maturitas 2007;56:249‐56.
Carranza‐Lira 2001 {published data only}
    1. Carranza‐Lira SC, Barahona OF, Ramos DP, Herrera J, Olivares‐Segura A, Cardoso G, et al. Changes in symptoms, lipid and hormone levels after the administration of a cream with phytoestrogens in the climacteric: preliminary report. International Journal of Fertility 2001;46(6):296‐9.
Caserta 2005 {published data only}
    1. Caserta L, Caserta R, Torella M, Nappo C, Lucia D, Panariello S. The effects of phytoestrogen therapy on the endometrium in postmenopausal women. Minerva Ginecologica 2005;57(5):551‐5.
Chandeying 2007 {published data only}
    1. Chandeying V, Sangthawan M. Efficacy comparison of Pueraria mirifica (PM) against conjugated equine estrogen (CEE) with/without medroxyprogesterone acetate (MPA) in the treatment of climacteric symptoms in perimenopausal women: Phase III study. Journal of the Medical Association of Thailand 2007;90(9):1720‐6.
Chandeying 2007a {published data only}
    1. Chandeying V, Lamlertkittikul S. Challenges in the conduct of Thai herbal scientific study: efficacy and safety of phytoestrogen, Pueraria mirifica (Kwao Keur Kao), phase I, in the alleviation of climacteric symptoms in perimenopausal women. Journal of the Medical Association of Thailand 2007;90(7):1274‐80.
Chiechi 2003 {published data only}
    1. Chiechi LM, Putignano G, Guerra V, Schiavelli MP, Cisternino AM, Carriero C. The effect of a soy rich diet on the vaginal epithelium in postmenopause: a randomized double blind trial. Maturitas 2003;45:241‐6.
Cianci 2012 {published data only}
    1. Cianci A, Cicero AFG, Colacurci N, Matarazzo MG, Leo V. Activity of isoflavones and berberine on vasomotor symptoms and lipid profile in menopausal women. Gynecological Endocrinology 2012;28(9):699‐702.
Cohn 2009 {published data only}
    1. Cohn RD, Bornhauser C, MacManus D, Sadakane M, Read W. A study of lavender and tea tree oils on postmenopausal FSH levels and hot flash severity. Journal of Clinical Oncology, 2009 ASCO Annual Meeting Proceedings 2009;27(15S):1516.
Colacurci 2004 {published data only}
    1. Colacurci N, Zarcone R, Borrelli A, Franciscis P, Fortunato N, Cirillo M, et al. Effects of soy isoflavones on menopausal neurovegetative symptoms. Minerva Ginecologica 2004;56(5):407‐12.
Dodin 2005 {published data only}
    1. Dodin S, Lemay A, Jacques H, Legare F, Forest J‐C, Masse B. The effects of flaxseed dietary supplement on lipid profile, bone mineral density and symptoms in menopausal women: a randomized, double‐blind, wheat germ placebo‐controlled clinical trial. Journal of Clinical Endocrinology and Metabolism 2004;90(3):1390‐7.
Duffy 2003 {published data only}
    1. Duffy R, Wiseman H, File SE. Improved cognitive function in postmenopausal women after 12 weeks of consumption of a soya extract containing isoflavones. Pharmacology, Biochemistry and Behaviour 2003;75:721‐9.
Duncan 1999 {published data only}
    1. Duncan AM, Underhill KEW, Xu X, LaValleur J, Phipps WR, Kurzer MS. Modest hormonal effects of soy isoflavones in postmenopausal women. Journal of Clinical Endocrinology and Metabolism 1999;84(10):3479‐84.
Ehsanpour 2012 {published data only}
    1. Ehsanpour S, Salehi K, Zolfaghari B, Bakhtiari S. The effects of red clover on quality of life in postmenopausal women. Iranian Journal of Nursing and Midwifery 2012;17(1):34‐40.
Erkkola 2010 {published data only}
    1. Erkkola R, Vervarcke S, Vansteelandt S, Rompotti P, Keeukeleire D, Heyerick A. A randomized, double‐blind, placebo‐controlled, cross‐over pilot study on the use of a standardized hop extract to alleviate menopausal discomforts. Phytomedicine 2010;17(6):389‐96.
Hale 2001 {published data only}
    1. Hale GE, Hughes CL, Robboy SJ, Agarwal SK, Bievre M. A double‐blind randomised study on the effects of red clover isoflavones on the endometrium. Menopause 2001;8(5):338‐46.
Harding 1996 {published data only}
    1. Harding C, Morton M, Gould V, McMichael Phillips D, Howell A, Bundred NJ. Dietary soy supplementation is oestrogenic in menopausal women (poster abstract). Second International Symposium on the role of soy in preventing and treating chronic disease, September 15‐18 1996, Brussels, Belgium. 1996.
Hochanadel 1999 {published data only}
    1. Hochanadel G, Shifren I, Zhdanova I, Maher T, Spiers P. Soy isoflavones (phytoestrogens) in the treatment of the cognitive and somatic symptoms of menopause. Fertility and Sterility 1999;71(4):22.
Ishiwata 2009 {published data only}
    1. Ishiwata N, Melby MK, Mizuno S, Watanabe S. New equol supplement for relieving menopausal symptoms: randomised, placebo‐controlled trial of Japanese women. Menopause 2009;16(1):141‐8.
Jenks 2012 {published data only}
    1. Jenks BH, Iwashita S, Nakagawa Y, Ragland K, Lee J, Carson WH, et al. A pilot study on the effects of S‐Equol compared to soy isoflavones on menopausal hot flash frequency. Journal of Women's Health 2012;21(6):674‐82.
Jou 2005 {published data only}
    1. Jou HJ, Ling PY, Wu SC. Comparison of 70mg and 35mg isoflavone soya supplement for menopause symptoms. International Journal of Gynaecology and Obstetrics 2005;90(2):156‐60.
Katz 2007 {published data only}
    1. Katz D, Evans M, Njike V, Hoxley M, Nawax H, Comerford B, et al. Raloxifene, soy phytoestrogens and endothelial function in postmenopausal women. Climacteric 2007;10(6):500‐7.
Kok 2005 {published data only}
    1. Kok L, Kreijkamp‐Kaspers S, Grobbee DE, Lampe JW, Schouw YT. A randomized placebo‐controlled trial on the effects of soy protein containing isoflavones on quality of life in postmenopausal women. Menopause 2005;12(1):56‐62.
    1. Kok L, Kreijkamp‐Kaspers S, Grobbee DE, Schouw YT. Design and baseline characteristics of a trial on health effects of soy protein with isoflavones in postmenopausal women. Maturitas 2004;47:21‐9.
Kolarov 2001 {published data only}
    1. Kolarov G, Nalbanski B, Kamenov Z. [Possibilities for an individualised approach to the treatment of climacteric symptoms with phytoestrogens] Bulgarian. Source not reported 2001;40:18‐21.
Krzysztof 2007 {published data only}
    1. Krzysztof D, Agnieszka S‐M, Ewa P, Agnieszka K‐S, Magdalena M, Agnieszka K. Efficacy of standardised isoflavones extract (Soyfem) (52‐104 mg/24h) in moderate and medium‐severe climacteric syndrome. Ginekologia Polska 2007;78:307‐11.
Lamlertkittikul 2004 {published data only}
    1. Lamlertkittikul S, Chandeying V. Efficacy and safety of Pueraria mirifica (Kwao Kruea Khao) for the treatment of vasomotor symptoms in perimenopausal women: phase II study. Journal of the Medical Association of Thailand 2004;87:33‐40.
Manonai 2006 {published data only}
    1. Manonai J, Songchitsomboon S, Chanda K, Hong JH, Komindr S. The effect of a soy‐rich diet on urogenital atrophy: a randomized crossover trial. Maturitas 2006;54:135‐40.
Manonai 2008 {published data only}
    1. Manonai J, Chittacharoen A, Udomsubpayakul U, Theppisai HY, Theppisai U. Effects and safety of Puerarua mirifica on lipid profiles and biochemical markers of bone turnover rates in healthy post‐menopausal women. Menopause 2008;15(3):530‐5.
Mittal 2011 {published data only}
    1. Mittal N, Hota D, Dutta P, Bhansali A, Suri V, Aggarwal N, et al. Evaluation of effect of isoflavone on thyroid economy and autoimmunity in oophorectomised women: a randomised, double‐blind, placebo controlled trial. Indian Journal of Medical Research 2011;133:633‐40.
Murkies 1995 {published data only}
    1. Murkies AL, Lombard C, Strauss BJG, Wilcox G, Burger HG, Morton MS. Dietary flour supplementation decreases postmenopausal hot flushes: effect of soy and wheat. Maturitas 1995;21:189‐95.
Nahas 2004 {published data only}
    1. Nahas EP, Neto JN, Luca L, Traiman P, Pontes A, Dalben I. Benefits of soy germ isoflavones in postmenopausal women with contraindication for conventional hormone replacement therapy. Maturitas 2004;48(4):372‐80.
Nasrin 2011 {published data only}
    1. Nasrin B, Azam A, Sedigheh A, Ahmad E, Habibollah E. Effect of powder of flaxseed on hot flashes in women at the climacteric. Iranian Journal of Obstetrics, Gynecology and Infertility 2011;14(1):37‐47.
Newton 2006 {published data only}
    1. Newton KM, Reed SD, Croix AZ, Grothaus LC, Ehrlich K, Guiltinan J. Principal results of the herbal alternatives for menopause (HALT) study. 16th Annual Meeting of the North American Menopause Society, San Diego, CA. 2005 September 28‐October 5:S‐13.
    1. Newton KM, Reed SD, LaCroix AZ, Grothaus LC, Ehrlich K, Guiltinan J. Treatment of vasomotor symptoms of menopause with black cohosh, multibotanicals, soy, hormone therapy or placebo. Annals of Internal Medicine 2006;145:869‐79.
    1. Reed SD, Newton KM, Grothaus L, Ehrlich K, Grieco V, Croix AZ. Vaginal findings from a randomized placebo‐controlled trial of black cohosh, multibotannical herbs and dietary soy for hot flushes: the herbal alternatives (HALT) study. 7th European Congress on Menopause, Istanbul, Turkey. 2006 June 3‐7:s102‐3.
    1. Reed SD, Newton KM, Grothaus L, Ehrlich K, Schenk J, Croix AZ. The herbal alternative for menopause study (HALT: dietary soy intervention). 7th European Congress on Menopause, Istanbul, Turkey. 2006 June 3‐7:s63.
    1. Reed SD, Newton KM, Croix AZ, Grothaus LA, Ehrlich K, Guiltinan K. The herbal alternatives for menopause (HALT) study: endometrial safety. 16th Annual Meeting of the North American Menopause Society, San Diego, CA. 2005 September 28‐October 5:P‐70.
    1. Reed SD, Newton KM, LaCroix AZ, Grothaus LC, Grieco VS, Ehrlich K. Vaginal, endometrial and reproductive hormone findings: randomised placebo‐controlled trial of black cohosh, multibotannical herbs, and dietary soy for vasomotor symptoms: the Herbal Alternatives for Menopause (HALT) study. Menopause 2008;15(1):51‐8.
Nikander 2005 {published data only}
    1. Nikander E, Rutanen E‐M, Nieminen P, Wahlstrom T, Ylikorkala O, Tiitinen A. Lack of effect of isoflavonoids on the vagina and endometrium in postmenopausal women. Fertility and Sterility 2005;83(1):137‐42.
Palacios 2010 {published data only}
    1. Palacios S, Pornel B, Vazquez F, Aubert L, Chantre P, Mares P. Long‐term endometrial and breast safety of a specific, standardized soy extract. Climacteric 2010;43(4):368‐75.
Pedro 2012 {published data only}
    1. Pedro AO, Carmigiani LO, Pinto‐Nero AM, Costa‐Paiva LS. The effect of a soy‐based dietary supplement on the vaginal epithelium and endometrium in postmenopause: a randomised double blind controlled clinical trial. Menopause 2012;19(12):1402‐3.
Pop 2008 {published data only}
    1. Pop E, Fischer L, Coan A, Gitzinger M, Nakamura J, Zeisel S. Effects of a high daily dose of soy isoflavones on DNA damage, apoptosis, and estrogenic outcomes in healthy postmenopausal women: a phase 1 clinical trial. Menopause 2008;15(4):684‐92.
Pruthi 2012 {published data only}
    1. Pruthi S, Qin R, Terstreip S, Liu H, Loprinzi C, Shah T, et al. A phase III, randomized, placebo‐controlled, double‐blind trial of flaxseed for the treatment of hot flashes: North Central Cancer Treatment Group N08C7. Menopause 2012;19(1):48‐53.
Quaas 2012 {published data only}
    1. Quaas AM, Kono N, Mack WJ, Hodis H, Paulson RJ, Shoupe D. The effect of isoflavone soy protein (ISP) supplementation on endometrial thickness, hyperplasia and endometrial cancer risk in postmenopausal women: a randomised controlled trial. Fertility and Sterility 2012;97(3 Suppl):S6 (abstract).
Quella 2000 {published data only}
    1. Quella SK, Loprinzi CL, Barton DL, Knost JA, Sloan JA, LaVasseur BI, et al. Evaluation of soy phytoestrogens for the treatment of hot flashes in breast cancer survivors: a North Central Cancer Treatment trial. Journal of Clinical Oncology 2000;18(5):1068‐74.
Rotem 2007 {published data only}
    1. Rotem CA, Kaplan B. Phyto‐female complex for the relief of hot flushes, night sweats and quality of sleep: randomised controlled double‐blind pilot study. Gynecological Endocrinology 2007;23(2):117‐22.
Russo 2003 {published data only}
    1. Russo R, Corosu R. The clinical use of a preparation based on phytoestrogens in the treatment of menopausal disorders. Acta Bio‐Medica de l Ateneo Parmense 2003;74(3):137‐43.
Sammartino 2006 {published data only}
    1. Sammartino A, Tommaselli GA, Gargano V, Carlo C, Attianese W, Nappi C. Short‐term effects of a combination of isoflavones, lignans and Cimicifuga racemosa on climacteric‐related symptoms in postmenopausal women: a double‐blind randomized placebo‐controlled trial. Gynecological Endocrinology 2006;22(11):646‐50.
Scambia 2000 {published data only}
    1. Scambia G, Mango D, Signorile PG, Angeli RA, Palena C, Gallo D, et al. Clinical effects of a standardized soy extract in postmenopausal women: a pilot study. Menopause 2000;7(2):105‐11.
Schwen 2010 {published data only}
    1. Scwen R, Griewe J, Desai P, Jackson R, Ausio Pharmaceuticals and Cincinnati College of Pharmacy. Development of S‐equol, a natural selective estrogen receptor beta agonist for the treatment of menopausal symptoms. Menopause 2010;17(6):12‐7.
Secreto 2003 {published data only}
    1. Secreto G, Chiechi LM, Amadori A, Miceli R, Venturelli E, Valerio T, et al. Soy isoflavones and melatonin for the relief of climcteric symptoms: a multicenter, double blind, randomized study. Maturitas 2004;47:11‐20.
Steinberg 2011 {published data only}
    1. Steinberg F, Murray M, Lewis R, Cramer M, Amato P, Young R, et al. Clinical outcomes of a 2‐y soy isoflavone supplementation in menopausal women. American Journal of Clinical Nutrition 2011;93(2):356‐67.
Uesugi 2004 {published data only}
    1. Uesugi S, Watanabe S, Ishiwata N, Uehara M, Ouchi K. Effects of isoflavone supplements on bone metabolic markers and climacteric symptoms in Japanese women. BioFactors 2004;22:221‐8.
Unfer 2004 {published data only}
    1. Unfer V, Casini ML, Costabile L, Mignosa M, Gerli S, Renzo GC. Endometrial effects of long‐term treatment with phytoestrogens: a randomized double‐blind placebo‐controlled study. Fertility and Sterility 2004;82(1):145‐8.
van Patten 2002 {published data only}
    1. Patten CL, Olivotto IA, Chambers GK, et al. Effect of soy phytoestrogens on hot flashes in postmenopausal women with breast cancer: a randomised controlled clinical trial. Journal of Clinical Oncology 2002;20(6):1449‐55.
Verhoeven 2005 {published data only}
    1. Verhoeven MO, Mooren MJ, Weijer PHM, Verhegem PJE, Burgt LMJ, Kenemans P. Effect of a combination isoflavones and Actaea racemosa Linnaeus on climacteric symptoms in healthy symptomatic perimenopausal women: a 12‐week randomized, placebo‐controlled, double‐blind study. Menopause 2005;12(4):412‐20.
Virojchaiwong 2011 {published data only}
    1. Virojchaiwong P, Suvithayasiri V, Itharat A. Comparison of Pueraria mirifica 25 and 50 mg for menopausal symptoms. Archives of Gynecology & Obstetrics 2011;284(2):411‐9.
Washburn 1999 {published data only}
    1. Washburn S, Burke GL, Morgan T, Anthony M. Effect of soy protein supplementation on serum lipoproteins, blood pressure, and menopausal symptoms in perimenopausal women. Menopause 1999;6(1):7‐13.
Woo 2003 {published data only}
    1. Woo J, Lau E, Ho SC, Cheng F, Chan C, Chan AS, et al. Comparison of Pueraria lobata with hormone replacement therapy in treating the adverse health consequences of menopause. Menopause 2003;10(4):352‐61.
Xue 2004 {published data only}
    1. Xue X, Niu J, Wang J, Ai H. A prospective controlled study on the clinical therapeutic effect of treatment of menstrual syndrome by isoflavone of soybean. Zhongguo Zhong Xi Yi Jie He Za Zhi 2004;24(9):835‐6.
Yang 2012 {published data only}
    1. Yang T‐S, Wang S‐Y, Yang Y‐C, Su C‐H, Lee F‐K, Chen S‐C, et al. Effects of standardised phytoestrogen on Taiwanese menopausal women. Taiwanese Journal of Obstetrics and Gynecology 2012;51(2):229‐35.
References to studies awaiting assessment Agrawal 2005 {unpublished data only}
    1. Agrawal S, Shah D. Phytoestrogens and quality of life. Royal College of Obstetricians and Gynaecologists 6th International Meeting, Cairo, Egypt. 2005 September 27‐30.
Baker 2011 {unpublished data only}
    1. Baker MB, Ciccone M, Wilson M, Stanczyk F, Shoupe D. A double‐blind placebo controlled trial on the effects of a licorice extract on menopausal symptoms. Fertility and Sterility 2011;96(3 Suppl):S5.
Garcia‐Martin 2012 {published data only}
    1. Garcia‐Martin A, Quesada Charneco M, Alvarez Guisado A, Jimenez Moleon JJ, Fonolla Joya J, Munoz‐Torres M. Effect of milk product with soy isoflavones on quality of life and bone metabolism. Medicina Clinica 2012;138(2):47‐51.
Mucowski 2013 {published data only}
    1. Mucowski SJ, Shoupe D, Dang H, Henderson V, Kono N, Hodis N, et al. The effect of soy isoflavones on menopausal vasomotor flushing. Fertility and Sterility 2012;99(Suppl 1):S35 (abstract).
Nahidi 2009 {published data only}
    1. Nahidi F, Zare E, Mojab F, Alavi Majd H. Effects of licorice root extract on the number of nocturnal hot flashes in menopausal women. Journal of Nursing and Midwifery 2009;19(67).
Paixao 2005 {published data only}
    1. Paixao JS, Fonseca AM, Bagnoli VR, Arie WMY, Penteado SRL, Junqueira PA, et al. Effects of genistein on endometrial thickness and climacteric symptoms: a double blind randomized controlled study. 16th Annual Meeting of North American Menopause Society, San Diego, CA, USA. 2005 September 28‐October 5.
Sekhavat 2012 {published data only}
    1. Sekhavat L, Firouzabadi RD. Effect of soya protein on symptoms of hot flash in menopausal women in Yazd, Iran. Iranian Journal of Obstetrics, Gynecology and Infertility 2012;15(6):10‐5.
Stanosz 2006 {published data only}
    1. Stanosz S, Puk E, Grobelny W, Stanosz M, Kazikowska A. Evaluation of the efficacy and tolerance of Soyfem in women in the early menopausal period [Polish]. Przeglad Menopauzalny 2006;5(3):182‐90.
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