| | Side Effects of Phytoestrogens: A Meta-analysis of Randomized TrialsAbstract BackgroundPhytoestrogens are widely used by postmenopausal women for the treatment of the climacteric syndrome. The risk of adverse effects of this treatment, however, is unknown. MethodsUsing a fixed-effects model, we performed a meta-analysis of side effects comparing phytoestrogen treatment with placebo or no treatment in randomized controlled trials. ResultsWe identified 174 randomized controlled trials. Side effects were reported in 92/174 randomized controlled trials with 9629 participants. The overall incidence of side effects in the phytoestrogen and control groups was 2019/5502 (36.7%) and 1824/4806 (38.0%), respectively (P =.2; incidence rate ratio [IRR] 1.01; 95% confidence interval [CI], 0.95-1.08). Comparing various side effect categories, we found significantly higher rates of gastrointestinal side effects among phytoestrogen users (P=.003; IRR 1.28; 95% CI, 1.08-1.50). Gynecological (IRR 0.94; 95% CI, 0.74-1.20), musculoskeletal (IRR 1.20; 95% CI, 0.94-1.53), neurological (IRR 0.91; 95% CI, 0.70-1.19), and unspecific side effects (IRR 0.95; 95% CI, 0.88-1.03) were not significantly different between groups. Within side effect categories, we found no significantly higher rates of side effects in women using phytoestrogens. Specifically, the rates of hormone-related side effects such as endometrial hyperplasia, endometrial cancer, and breast cancer were not significantly different between groups. ConclusionsBased on the available evidence, phytoestrogen supplements have a safe side-effect profile with moderately elevated rates of gastrointestinal side effects. Rates of vaginal bleeding, endometrial hyperplasia, endometrial cancer, and breast cancer were not significantly increased among phytoestrogen users in the investigated studies. Phytoestrogens are widely used by women for the treatment of climacteric syndrome complaints. Data from large-scale randomized trials and epidemiologic studies such as the Womens' Health Initiative and the One Million Women Study have challenged the safety of hormone replacement therapy and have led to an increased interest in phytoestrogens as an alternative treatment of the climacteric syndrome. Generally, phytoestrogens can be divided into 3 groups: flavonoids such as genistein, naringenin, and kaempferol; coumestans such as coumestrol; and lignans such as enterodiol and enterolactone. The best-studied phytoestrogenic compounds are isoflavones found in red clover and soy, for example, genistein, formononentin, biochanin A, and daidzein.1 Clinical Significance•Phytoestrogen supplements have a safe side effect profile. •In phytoestrogen supplement users, gastrointestinal side effects occur more often, compared with placebo or no treatment. •Among phytoestrogen users in the investigated studies, there was no significant increase in rates of vaginal bleeding, endometrial hyperplasia, endometrial cancer, and breast cancer. It has been demonstrated that phytoestrogens are weak estrogen agonists acting via the estrogen receptor alpha and beta as well as through alternative signaling pathways in a receptor- and cell type-specific manner. The relative affinities of phytoestrogens to the estrogen receptor alpha as well as estrogen receptor beta are more than 1000-fold lower than that of estradiol.2 Some phytoestrogens, for example, zearalenone, also exhibit estrogen antagonistic activity, but most phytoestrogens, including the flavonoids present in soy foods, only show agonistic activities. Therefore, systemic treatment with phytoestrogens can be expected to exert weak estrogen agonistic effects on various tissues. Whether or not treatment with phytoestrogens is associated with unwanted hormone-related side effects such as endometrial hyperplasia, endometrial cancer, and breast cancer, is unknown. Based on these biologic properties of phytoestrogens, the safety of phytoestrogen supplementation has been challenged. Genistein, for example, antagonizes the inhibitory effect of tamoxifen on breast cancer cell growth in vivo and increases expression of estradiol-responsive genes.3 Likewise, genistein negates the inhibitory effect of letrozole on the growth of aromatase-expressing human breast cancer cells.4 Genistein and daidzein stimulate the formation of genotoxic metabolites of estradiol and inhibit the detoxification of catechol and quinone estrogens in estrogen-responsive tumor cells. Soy isoflavones decrease the catechol-O-methyltransferase-mediated inactivation of 4-hydroxyestradiol in human breast cancer cell lines such as MCF-7.5 These experimental effects, however, are dose-dependent, and it is unclear whether these in vitro properties of phytoestrogens translate into an increased risk of hormone-related side effects such as endometrial cancer and breast cancer in women using phytoestrogens. To clarify the safety profile of phytoestrogens in this regard, we aimed to summarize the side effects and adverse events of phytoestrogen supplements reported in randomized controlled trials. Materials and Methods  Study Selection We searched PubMed and the Cochrane controlled trials register (search terms: phytoestrogens, isoflavones, treatment, clinical trial, randomized) to identify randomized controlled trials, systematic reviews, and meta-analyses of randomized controlled trials assessing phytoestrogen teatment. Studies were included if they were published as original reports in English. Side effects and adverse events were summarized in each study. We included only studies assessing women. Studies assessing women and men were included, if the participating women were analyzed separately. Side effects were counted per side effect, that is, individual women could have more than one side effect. In cross-over studies, side effects were counted per side effect in all treatment groups. Multiple studies describing the same study population were included once. In this case, the original publication was used, that is, the one with the earliest date of publication. Phytoestrogens were defined as substances with a defined amount of isoflavones, lignans, or coumestans. Two authors assessed eligibility of the studies and extracted data. Missing information and additional trials were not sought from authors. We recorded the adequacy of treatment allocation concealment and considered trials to have adequate concealment if they described satisfactory procedures to conceal treatment allocation such as coded identical containers or centralized randomization. We also recorded blinding of participants and outcome assessors, use of intention-to-treat analysis, and the number of participants who withdrew or were lost to follow-up. For each study and each type of side effects, we computed an incidence rate ratio (IRR) as follows: IRR=incidence rate in the phytoestrogen group/incidence rate in control group. The incidence rate was defined as the number of side effects reported divided by person-time. Because of the large proportion of studies reporting zero side effects of some type, we added 0.5 to the number of side effects and 1 to the number of patients in each group to yield finite incidence rate ratios. The variance of the logarithm of IRR (logIRR) was computed as: The standard error was calculated by the square root of the variance; 95% confidence intervals for individual IRRs were computed by exp (logIRR±1.96 standard errors). We used IRRs instead of odds ratios or relative risks because the number of reported side effects was potentially larger than the sample size, because the same participant may have reported several side effects. IRRs of individual studies were combined using a weighted mean of logIRR with weights given by the reciprocal variance of each study. A fixed-effects model was used for meta-analysis because no heterogeneity was detected (P >.9 in all analyses). Our analysis did not consider dependency of multiple side effects reported by the same patient because this information was not available. For specific side effects, we computed exact P-values by randomly distributing the recorded incidences of each study between groups, generating 100,000 permutations of the IRR under the null hypothesis of no group difference; and computing a P-value as the relative frequency of permuted IRRs as extreme as or more extreme than the IRR observed in the original data. These exact P-values were then corrected for multiple testing by Benjamini and Hochberg's correction.6 The influence of clinical and epidemiologic variables such as patient age, region of study origin, phytoestrogen dosage, duration of phytoestrogen therapy, and mode of control group design (placebo vs. no treatment) on the occurrence of side effects was assessed using analysis of variance with the logIRR as dependent variable, weighting the studies by the reciprocal standard error. For all statistical analyses, we used the R package rmeta (R Foundation for Statistical Computing, Vienna, Austria, 2008). Results We identified 174 randomized controlled trials comparing phytoestrogen treatment with placebo or no treatment in women. In 82/174 studies, no side effects or adverse events were reported. These studies were excluded from the analysis. Side effects were reported in 92 randomized controlled trials.7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 Median treatment duration in these trials was 6.2 months. Table 1 (available online) describes study details of the 92 randomized controlled trials included in the analysis. Overall, 9629 women were investigated, with 5502 and 4806 women in the phytoestrogen and control groups (including cross-over trials), respectively. The overall incidence of side effects in the phytoestrogen and control groups was 2019/5502 (36.7%) and 1824/4806 (38.0%), respectively (P=.2; IRR 1.01; 95% CI, 0.95-1.08). Figure 1 demonstrates a Forest plot of side effects in 92 studies comparing women taking phytoestrogens and controls. Table 2 lists side effects in the phytoestrogen and control groups broken down in various side effect categories: gynecological, gastrointestinal, musculoskeletal, neurological, and others. Specifically, we found that there was a statistically significant difference between the phytoestrogen and control groups regarding the frequency of gastrointestinal side effects (P=.003; IRR 1.28; 95% CI, 1.08-1.50), but not gynecological (IRR 0.94; 95% CI, 0.74-1.20), musculoskeletal (IRR 1.20; 95% CI, 0.94-1.53), neurological (IRR 0.91; 95% CI, 0.70-1.19), and unspecific side effects (IRR 0.95; 95% CI, 0.88-1.03). Figure 2 demonstrates a funnel plot indicating that there was no publication bias regarding the incidence of side effects. Figure 3 demonstrates a Forest plot of the IRRs of side effects according to different study characteristics such as patient age, region of study origin, phytoestrogen dosage, duration of phytoestrogen therapy, and mode of control group design (placebo vs no treatment), demonstrating that patient age and region of study origin, but not phytoestrogen dosage, duration of phytoestrogen therapy, and mode of control group design (placebo vs no treatment) affected the risk of side effects. | | |  | First Author (Year of Publication) | Participants (Withdrawn) | Inclusion Criteria | Participant Characteristics | Study Duration | Study Medication | |
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| Albertazzi (2005)7 | 100(1) | Amenorrhea ≥12 mos and ≤10 years; HRT ex ≥1 year; No secondary causes of bone loss | | 6wks | Capsules (90 mg/d genistein) | | | Albertazzi (1998)8 | 104(25) | Amenorrhea ≥6 mos or Oophorectomy ≥6 wks; ≥7 HF/d; FSH >50 IU/L; E2 <35 pg/mL HRT ex ≥6 wks | | 12wks | Soy protein (76 mg/d isoflavones) | | | Allen (2007)9 | 216(25) | Amenorrhea ≥12 mos or FSH >30 IU/L and LDL 3.37-4.92 nmol/L or Triglycerides >1.7 nmo/L; | | 12wks | Soy protein (160 mg/d isoflavones) | | | Arjmandi (2005)10 | 87(25) | Postmenopausal; Age <65 years; No HRT; | | 12mos | Soy protein (60 mg/d isoflavones) | | | Arjmandi (2003)11 | 71(29) | Postmenopausal | | 3mos | Soy protein (88.4 mg/d isoflavones) | | | Atkinson (2004)12 | 205(28) | Age 49-65 years; Breast density | | 12mos | Promensil® (Red Clover; 43.5 mg/d isoflavones) | | | Atteritano (2007)13 | 389(85) | Age 49-67 years; Amenorrhea ≥12 mos; Good general health; FSH >50 IU/L; E2 <100 pmol/L; BMD at femoral neck <0.795g/cm2 | | 24mos | Tablets (54 mg/d genisteinisoflavone) | | | Aubertin-Leheudre (2007)14 | 24(6) | Age 50-70 years; Amenorrhea ≥12 mos; BMI >28; Waist circumference >88 cm; HRT ex ≥12 mos; Weight stable for 2 mos; Non-smoker; No medication that could influence glucose or lipid metabolism | | 6mos | Soy capsules (70 mg/d isoflavones) | | | Balk (2002)15 | 27(8) | Age >40 years and Amenorrhea ≥12 mos or Age >30 years and Oophorectomy/ovarian failure; Intact uterus; Omnivorous | | 6mos | Soy flour (100 mg/d isoflavones) | | | Blum (2003)16 | 30(6) | Postmenopausal; Hypercholesterolemia; HRT ex ≥2 mos; LDL>130 mg/dL; | | 6wks | Soy protein (25g/d) | | | Brink (2008)17 | 300(63) | Amenorrhea 12-60 mos; FSH >20 IU/L; Non-osteoporotic; BMI 22-29 kg/m2; | | 12mos | Soy protein (110 mg/d isoflavones) | | | Burke (2002)18 | 49(7) | Age 18-48 years; Active menstruation; Non-complex migraine without aura; Migrain attacks >1 year; Migrain attacks/mos ≥3 | | 28wks | Combination (60 mg/d soy isoflavones; 100 mg/d dong quai; 50 mg/d black cohosh) | | | Campagnoli (2005)19 | 61(14) | Age 45-58 years; BMI 18-28 kg/m2; Surgical menopause or bilateral ovariectomy ≥3 mos or Amenorrhea >6 mos with E2 <30 pg/mL and FSH >40 IU/L; ≥5 HF/d | | 12wks | Soy capsules (60 mg/d isoflavones±PUFA) | | | Cancellieri (2007)20 | 142(17) | Postmenopausal; Age 45-65 years; No pharmacological treatment <30 d | | 6mos | Combination (Soy extract, red clover and black cohosh; 72 mg/d isoflavones) | | | Casini (2006)21 | 78(2) | Intact uterus; Amenorrhea ≥12 mos; FSH >30 IU/L; E2 <10 pg/mL; | | 6mos | Soy Protein (60 mg/d isoflavones) | | | Chen (2003)22 | 203(26) | Age 48-62 years; Amenorrhea ≥12 mos; | | 12mos | Soy extract (40 mg/d or 80 mg/d isoflavones) | | | Chiechi (2002)23 | 187(58) | Amenorrhea ≥6 mos, FSH >30 IU/L and E2 <20 pg/mL or bilateral ovariectomy | | 6mos | Soy protein (47 mg/d isoflavones) | | | Colacurci (2005)24 | 60(3) | | | 6mos | Tablets (60 mg/d isoflavones) | | | D'Anna (2005)25 | 90(9) | Age 50-60 years; Amenorrhea ≥12 mos; FSH >50 IU/L | | 6mos | Tablets (54 mg/d genistein isoflavone) | | | Davis (2001)26 | 78(23) | Non-asian women; Age 45-70 years; Lived in Australia ≥10 years; Amenorrhea ≥12 mos; FSH >25 IU/L; ≥14 HF/wk | | 12wks | Chinese medical herbs | | | Dodin (2005)27 | 199(43) | Age 45-65 years; FSH ≥40 IU/L; Amenorrhea ≥6 mos; Normal mammogram <2 years; | | 12mos | 40 g/d flaxseed | | | Faure (2002)28 | 75(20) | ≥7 HF/d; FSH >40 IU/L; E2 <35 pg/mL; HRT ex ≥6 wks | | 4mos | Soy extract (70 mg/d isoflavones) | | | Frei-Kleiner (2005)29 | 127(15) | Age 45-60 years; ≥3 HF/d; ≥1 functioning ovary; climacteric disorders | | 12wks | C. racemosa (42 mg/d crude drug) | | | Gallagher (2004)30 | 65(15) | Amenorrhea ≥12 mos or FSH >35 IU/L and E2 <30 pg/mL | | 9mos | Soy protein (96 mg/d or 52 mg/d isoflavones) | | | Gardner (2001)31 | 100(6) | Amenorrhea ≥12 mos; Age <80 years; BMI 20-31 kg/m2 | | 12wks | Soy Protein (3 mg/d or 80 mg/d isoflavones) | | | Garrido (2006)32 | 29(0) | Age 45-60 years; Amenorrhea ≥6 mos; FSH >20 IU/L; HRT ex >6 mos | | 12wks | Soy protein (100 mg/d isoflavones) | | | González (2007)33 | 32(6) | | | 12wks | Soy protein (132 mg/d isoflavones) | | | Hale (2002)34 | 32(3) | Age 45-70 years; Amenorrhea ≥12 mos; HRT ex ≥6 mos; ≥6 mos no Antibiotics; ≥12 mos no smoking; BMI <35 kg/m2 | | 2wks | Soy protein (80 mg/d isoflavones) | | | Hallund (2006)35 | 23(1) | Amenorrhea ≥24 mos; ≥6 mos no HRT; ≥3 mos no Antibiotics | | 6wks | Lignan Complex (500 mg/d) | | | Han (2002)36 | 82(2) | Age 45-55 years; Amenorrhea ≥12 mos; ≥12 mos no HRT; intact uterus; FSH >25 IU/L; E2 <20 pg/mL; HF | | 4mos | (100 mg/d isoflavones) | | | Harkness (2004)37 | 20(1) | Amenorrhea >8 years; Age >50 years; ≥3 mos no HRT | | 6mos | Soy protein (110 mg/d isoflavones) | | | Heyerick (2006)38 | 67(12) | Age 45-60 years; Intact uterus; Amenorrhea ≥12 mos; ≥3 mos no HRT; 2-5 HF/d | | 12wks | Hop extract (100 μg/d or 250 μg/d 8-PN) | | | Hidalgo (2005)39 | 60(7) | Amenorrhea >12 mos; Age >40 years; No HRT | | 90days | Red Clover (80 mg/d isoflavones) | | | Hirata (1997)40 | 71(10) | Amenorrhea ≥6 mos; Troublesome night sweats | | 24wks | Dong quai extract (4.5 g/d) | | | Ho (2007)41 | 200(23) | Age 55-75 years; Amenorrhea ≥5 years; BMI 18-32 kg/m2; ≥6 mos no HRT | | 6mos | Soy protein (80 mg/d isoflavones) | | | Ho (2007)42 | 203(29) | Age 48-62 years; Amenorrhea ≥12 mos or <10 years | | 12mos | Soy protein (40 mg/d or 80 mg/d isoflavones) | | | Howes (2004)43 | 30(2) | Age >60 years; Amenorrhea ≥5 years no HRT (ever) | | 6mos | Rimostil® (Red Clover; 80 mg/d isoflavones) | | | Izumi (2007)44 | 26(0) | Age 35-45 years | | 12wks | Soy protein (40 mg/d isoflavones) | | | Jacobson (2001)45 | 85(16) | Age >18 years; ≤2 mos before treated for breast cancer (chemo-/radiotherapy) | | 2mos | C. racemosa | | | Jayagopal (2002)46 | 33(1) | | | 12wks | Soy protein (132 mg/d isoflavones) | | | Katz (2007)47 | 25(3) | Amenorrhea ≥12 mos; FSH >40 IU/L; E2 <25 pg/mL non-smoker; normolipidemic | | 6wks | Soy protein (55-65 mg/d isoflavones) | | | Khaodhiar (2008)48 | 191(44) | Amenorrhea ≥6 mos; Age 38-60 years; ≥4 HF/d | | 12wks | Soft-gel Capsules (40 mg/d or 60 mg/d isoflavones) | | | Knight (2001)49 | 24(4) | Amenorrhea ≥6 mos, FSH >40 IU/L or bilateral oopherectomy; Age 40-65 years; ≥3 HF/d | | 12wks | TakeCare® (134.4 mg/d isoflavones, 77.4 mg/d aglycone) | | | Kotsopoulos (2000)50 | 94(19) | Age 50-75 years; Amenorrhea ≥12 mos; FSH >20 IU/L; ≥12 mos no HRT; ≥3 mos no antibiotics; non-smokers; non-vegetarian | | 3mos | Soy protein (118 mg/d isoflavones) | | | Kreijkamp-Kaspers (2004)51 | 202(49) | Age 60-75 years; ⊥mammogram <1 year; Amenorrhea | | 12mos | Soy protein (99 mg/d isoflavones) | | | Kumar (2002)52 | 97(31) | Age 25-55 years; BMI <38 kg/m2; no HT | | 12wks | Soy protein (40 mg/d isoflavones) | | | Lampe (2001)53 | 26(6) | Age 20-40 years; regular menstrual cyclus; ≥4 mos no antibiotics; no HT | | 1mo | Soy protein (110 mg/d isoflavones) | | | Lewis (2006)54 | 99(11) | Age 45-60 years; Postmenopausal ≥12 mos and <8 years | | 16wks | Flaxseed (50 mg/d lignans) or Soy Protein (42 mg/d isoflavones) | | | Lucas (2002)55 | 58(22) | Postmenopausal; Age <65 years; no HRT | | 3mos | Flaxseed (40g/d) | | | Lydeking-Olsen (2004)56 | 107(18) | Amenorrhea ≥12 mos; Age <75 years; ≥2 years no bone-active medication; ≥3 risk-criteria for osteoporosis; | | 24mos | Soymilk (76 mg/d isoflavones) | | | MacGregor (2005)57 | 72(25) | Age >18 years; Histological confirmed pre-existing breast cancer; menopausal symptoms | | 12wks | Soy capsules (70 mg/d isoflavones) | | | Maesta (2007)58 | 60(14) | Amenorrhea ≥12 mos; FSH >40 IU/L; Age 45-70 years | | 16wks | Soy protein (50 mg/d isoflavones) | | | Martini (1999)59 | 40(2) | Age 18-40 years; ≥6 mos no antibiotics | | 2mos | Soy product (38 mg/d isoflavones) | | | Maskarinec (2004)60 | 220(31) | Normal mammogram no OC or HAT; intact uterus | | 24mos | Soy protein (50 mg/d isoflavones) | | | Maskarinec (2002)61 | 34(5) | Age 35-46 years; ⊥mammogram <6 mos; ≥3 mos no OC or HAT; intact uterus; regular menstrual periods | | 12mos | Soy protein (100 mg/d isoflavones) | | | Morabito (2002)62 | 90(-) | Age 47-57 years; Amenorrhea ≥12 mos; FSH >50 IU/L; E2 <100 pmol/L | | 12mos | Tablets (54 mg/d genistein isoflavone) | | | Nahas (2004)63 | 50(0) | Amenorrhea ≥12 mos; FSH >40 IU/L; HF; Contraindication or intolerance to HRT | | 6mos | Soy Germ (60 mg/d isoflavones) | | | Nahas (2007)64 | 80(4) | Age ≥45 years; Amenorrhea ≥12 mos; FSH >40 IU/L; ≥5 HF/d | | 10mos | Soy extract (100 mg/d isoflavones) | | | Newton (2006)65 | 351(45) | Age 45-55 years; Amenorrhea ≥12 mos; FSH >20 IU/L; ≥2 vasomotors symptoms per day | | 12mos | C. racemosa (160 mg/d) or MB+C. racemosa (200 mg/d) or MB+soy | | | Nikander (2003)66 | 62(6) | Climacteric complaints; FSH >30 IU/L; Postmenonpausal | | 3mos | Soy protein (114 mg/d isoflavones) | | | Osmers (2005)67 | 304(36) | Amenorrhea ≥12 mos or Amenorrhea ≥6 mos with FSH ≥50 IU/L; Age ≥45 years; Climacteric complaints | | 12wks | Remifemi® (C. racemosa; 2.5 mg/d isopropanolic) | | | Penotti (2003)68 | 62(13) | Age 45-60 years; Amenorrhea ≥6 mos; LDL <160 mg/dL | | 6mos | Soy protein (72 mg/d isoflavones) | | | Pockaj (2006)69 | 132(33) | ≥14 HF/wk; history or increased risk of breast cancer | | 4wks | C. racemosa (20 mg/d) | | | Quella (2000)70 | 177(28) | Age >18 years; History of breast cancer (currently without evidence of residual malignant disease; ≥14 HF/wk; | | 4wks | Soy protein (50 mg/d isoflavones) | | | Rad (2006)71 | 24(-) | BMI 19-29 kg/m2; Age 46-65 years; Amenorrhea ≥12 mos | | 2days | C. racemosa (50 mg/d, 250 mg/d or 750 mg/d 8-PN) | | | Reimann (2006)72 | 99(10) | Age 45-70 years; Amenorrhea ≥12 mos; ≥6 mos no HRT; ≥3 mos no antibiotics | | 8wks | Soy protein (50 mg/d isoflavones) | | | Ritchie (2004)73 | 15(0) | Age 30-51 years; Regular menstrual cycle | | 6mos | Soy protein 35 mg/d isoflavones) | | | Russo (2003)74 | 50(3) | Age 48-54 years; Amenorrhea ≥12 mos and ≤3 years; neg. PAP test; ET ≤4 mm; Caucasian race; Climacteric complaints | | 3mos | Fitormil® (32 mg/d isoflavones) | | | Samman (1999)75 | 21(7) | Age 18-45 years; Regular menstrual cycle; no HAT or OC | | 2mos | Red clover (86 mg/d isoflavones) | | | Sammartino(2003)76 | 70(7) | Amenorrhea ≥12 mos; FSH >40 IU/L; E2 <20 pg/mL; ≥7HF/d | | 12mos | Fitogen® (36 mg/d isoflavones) | | | Sammartino (2006)77 | 80(5) | Amenorrhea ≥6 mos and ≤2 years; FSH >40 IU/L; ≥7 HF/d; BMI 18-30 kg/m2 | | 3mos | Soy germ (60 mg/d isoflavones) andlignans (20 mg/d flaxseed) and C. racemosa (1.25 mg/d) | | | Schult (2004)78 | 252(6) | Age 45-60 years; ≥35 HF/wk; Amenorrhea ≥6 mos or bilateral oopherectomy; FSH ≥30 IU/L | | 12wks | Promensil® (82 mg/d isoflavones) or Rimostil® (57.2 mg/d isoflavones) | | | Secreto (2004)79 | 262(30) | Amenorrhea ≥6 mos; Age ≥35 years; ≥3 mos no HRT | | 3mos | Soy (80 mg/d isoflavones) or soy+melatonin or melatonin (3 mg/d) | | | Simons(2000)80 | 23(3) | Age 50-70 years; Amenorrhea ≥12 mos; Non-smoking; Cholesterol <8 mmol/L; Triglycerides <3 mmol/L | | 8wks | Soy protein (80 mg/d isoflavones) | | | Sites (2007)81 | 18(3) | Amenorrhea ≥12 mos and ≤5 years; FSH >30 IU/L | | 3mos | Soy protein (160 mg/d isoflavones) | | | Squadrito (2003)82 | 90(11) | Age 52-60 years; Amenorrhea ≥12 mos; No surgical menopause; FSH >50 IU/L; E2 ≤100 pmol/L | | 12mos | Genistein (54 mg/d) | | | Squadrito (2002)83 | 60(0) | Age 52-60 years; Amenorrhea ≥12 mos; No surgical menopause; FSH >50 IU/L; E2 ≤100 pmol/L | | 6mos | Genistein (54 mg/d) | | | St Germain (2001)84 | 80(11) | Amenorrhea ≥12 mos; ≥10 HF/wk; ≥12 mos no HT; BMI 20-31 kg/m2 | | 6mos | Soy Protein (4.4 mg/d or 80.4 mg/d isoflavones) | | | Steinberg (2003)85 | 42(14) | Amenorrhea ≥12 mos; FSH ≥23 IU/L; ≥6 mos no HRT; BMI <30 kg/m2 | | 6wks | Soy protein (2 mg/d or 107 mg/d isoflavones) | | | Uesugi (2002)86 | 23(0) | Age 40-62 years; perimenopausal | | 4wks | Soy protein (61.8 mg/d isoflavones) | | | Unfer (2004)87 | 376(78) | Intact uterus; Amenorrhea ≥12 mos; FSH ≥30 IU/L | | 5years | Soy protein (150 mg/d isoflavones) | | | Upmalis (2000)88 | 177(55) | Amenorrhea ≥6 mos; Age ≥50 years; FSH ≥30 IU/L; E2 ≤25 pg/mL; ≥5 vasomotor symptoms/d; ≥60 d no HRT | | 12wks | Soy protein (50 mg/d isoflavones) | | | Van de Weijer (2002)89 | 42(12) | Age 49-65 years; Amenorrhea ≥12 mos; ≥12 wks no HT or antibiotics | | 12wks | Promensil® (82 mg/d isoflavones) | | | Van Patten (2002)90 | 157(34) | Amenorrhea ≥12 mos; ≥4 mos no HRT; ≥10 HF/wk; history of breast cancer (>4 mos since completion of treatment) | | 12wks | Soy protein (90 mg/d isoflavones) | | | Verhoeven(2005)91 | 124(8) | Amenorrhea ≥6 mos; FSH >25 IU/L; | | 12wks | Soy extract (50 mg/d isoflavones) andC. racemosa (8 mg/d deoxyacetein) and primrose oil (1500 mg/d) | | | Vigna (2000)92 | 104(27) | Amenorrhea ≥6 mos or Bilateral oopherectomy ≤6 wks; >7 HF/d; FSH >50 IU/L; E2 <130 pmol/L; ≥6 wks no HT | | 12wks | Soy protein (76 mg/d isoflavones) | | | Wiklund (1999)93 | 384(5) | Age 45-65 years; ≥2 mos no HRT; Amenorrhea ≥6 mos | | 16wks | Ginsana® (100 mg/d ginseng extract) | | | Wu (2006)94 | 136(8) | Age 45-60 years; Amenorrhea ≥12 mos and ≤5 years; no HRT or antibiotics | | 24wks | 75 mg/d isoflavones | | | Xu (1995)95 | 7(0) | Omnivorous; Good general health | | 3days | Soymilk (3.4 or 6.9 or 10.3 μmol/kg/d isoflavones) | | | Xu (2000)96 | 18(-) | Omnivorous; Good gerneral health | | 1day | Soymilk (0.9 mg/d/kg isoflavones) | | | Ye (2006)97 | 90(8) | Age 45-60 years; Amenorrhea ≥12 mos and ≤5 years; FSH >30 IU/L | | 6mos | Soy protein (84 mg/d or 126 mg/d isoflavones) | | | Zhang (2007)98 | 100(15) | Amenorrhea 10-18 years; BMD 0.968-1.014g/cm2 at lumbar spine | | 24mos | Epimedium-derived Phytoestrogen flavonoids (78 mg/d isoflavones) | | | | |
We separately evaluated the effect of study duration on the occurrence of side effects. When comparing the IRRs of side effects in studies with a study duration of <6 months vs. >6 months (IRR 1.14; 95% CI, 0.92-1.03 [54 studies] vs IRR 0.93; 95% CI, 1.00-1.09 [38 studies]; P=.7), <12 months vs >12 months (IRR 0.98; 95% CI, 1.08-1.19 [76 studies] vs IRR 0.88; 95% CI, 0.96.1.05 [16 studies]; P=.04), and <24 months vs ≥24 months (IRR 0.97; 95% CI, 1.04-1.12 [87 studies] vs IRR 0.74; 95% CI, 0.86-1.01 [5 studies]; P=.01), we found that women using phytoestrogens for a longer period of time reported fewer side effects than women enrolled in studies with a shorter study duration. Table 3, Table 4 describe gynecological and gastrointestinal side effects in detail. Within these side effect categories, we found no significantly higher rates of side effects in women taking phytoestrogens compared with controls. Specifically, the rates of hormone-related side effects such as endometrial hyperplasia (13 vs 6 cases; P=.6) and breast cancer (11 vs 5 cases; P=.9) were not significantly different between women taking phytoestrogens and controls. One case of endometrial cancer was recorded in the investigated studies diagnosed 2.8 months after study entry.65 Newly diagnosed breast cancer cases were observed 4.7, 6, 12, 15, and 24 months after study entry. Both low- and high-dose preparations were used, and there was no pattern regarding a diagnosis of breast cancer preferentially in women after a longer duration of phytoestrogen use. | | | | | Vaginal Bleeding | Vaginal Spotting | Nipple Discharge | Breast Pain, Enlargement or Mastodynia | Breast Cancer (Breast Cancer Recurrence) | Endometrial Hyperplasia | Pelvic Discomfort | Nycturia | Others or Undefined | |
|---|
| Phytoestrogens (n=5502) | 48 | 5 | 0 | 12 | 11(2) | 14 | 1 | 1 | 48 | | | Controls (n=4806) | 29 | 1 | 0 | 5 | 5(0) | 6 | 0 | 0 | 48 | | | P-value | 0.9 | 0.4 | — | 1.0 | 0.9(0.9) | 0.6 | 1.0 | 1.0 | 1.0 | | | | |
| | | | | Constipation | Diarrhea | Gastroenteritis | Bloating or Flatulence | Nausea or Vomiting | Abdominal Pain | Dyspepsia | Epigastric Pain | Others or Undefined | |
|---|
| Phytoestrogens (n=5502) | 69 | 7 | 7 | 55 | 35 | 27 | 12 | 7 | 141 | | | Controls (n=4806) | 57 | 6 | 2 | 36 | 22 | 9 | 4 | 0 | 107 | | | P value | 0.9 | 1.0 | 0.4 | 0.6 | 0.2 | 0.2 | 0.3 | 0.2 | 0.9 | | | | |
As to the qualitative analysis of the investigated studies, we found that 82/92 studies had adequate concealment of treatment allocation7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 24, 25, 26, 28, 29, 30, 31, 32, 33, 34, 35, 36, 38, 39, 40, 41, 42, 43, 45, 46, 47, 48, 49, 50, 51, 52, 54, 55, 56, 57, 58, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 97, 98 and 21/92 studies had centralized randomization.7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 19, 21, 22, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 Blinding of participants and outcome assessors was performed in 81/92 trials,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 74, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 98 whereas blinding of participants but not outcome assessors, was performed in 11/92 trials.23, 43, 58, 59, 60, 73, 75, 76, 95, 96, 97 In 58/92 studies, >10% of study participants withdrew or were lost to follow-up.8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 22, 23, 26, 27, 28, 29, 30, 33, 38, 39, 40, 41, 42, 45, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 60, 61, 65, 67, 68, 69, 70, 72, 75, 78, 79, 80, 81, 82, 84, 85, 87, 88, 89, 90, 92, 9892, 98 Intention-to-treat analysis was reported in 21/92 studies.13, 18, 19, 27, 28, 29, 41, 42, 43, 45, 49, 51, 52, 54, 57, 67, 77, 89, 91, 93, 98 Dropout rates were reported in 90/92 studies.7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 97, 98 The number of dropouts in the phytoestrogen and control groups was not statistically significantly different (646/5454 vs 525/4758, respectively [P=.2]). Side effects of the study medication, however, were cited significantly more often as reason for dropout by women using phytoestrogens, compared with controls (199/5454 and 125/4758 of patients, respectively [P=.004]). In individual studies, a statistically significant difference in the incidence of side effects between the phytoestrogen and control groups was reported in 2/92 randomized controlled trials.7, 87 Specifically, Albertazzi et al. reported significantly higher rates of bloatedness (7 vs 0 cases) and back pain (10 vs 2 cases) in a 12-week cross-over study of 100 postmenopausal women comparing 90 mg of genistein per day with placebo.7 One long-term study over 5 years examined 298 women and reported a higher rate of endometrial hyperplasia without atypia in women taking 150 mg of isoflavone tablets per day compared with placebo (6 vs 0 cases, respectively). Specifically, all 5 cases of simple hyperplasia and 1 case of complex hyperplasia occurred after 5 years of treatment. No cases of endometrial hyperplasia with atypia or endometrial carcinoma were observed in this study.87 Discussion Phytoestrogens are widely used by peri- and postmenopausal women for the treatment of the signs and symptoms of the climacteric syndrome. The risk of adverse effects of this treatment, however, is unknown. Specifically, a potential risk of hormone-related side effects such as endometrial and breast cancer is of concern because phytoestrogens have been demonstrated to act as weak estrogen agonists. Therefore, in the present study, we identified and analyzed 92 randomized controlled trials with 9629 participants regarding the occurrence of side effects of phytoestrogen treatment compared with placebo. We found that, based on the available evidence, phytoestrogen supplements have a safe side-effect profile with moderately elevated rates of gastrointestinal side effects such as abdominal pain, as well as myalgia and sleepiness. Phytoestrogen supplementation is not associated with an increased risk of breast or endometrial cancer. We observed that the incidence rate ratio of side effects is affected by the region of study origin and patient age. Compared with studies from the US and Europe, studies conducted in Asia were more likely to record higher side effect rates in phytroestrogen-treated women than in controls. Also, phytoestrogen-treated women aged >55 years had higher rates of side effects compared with women aged <55 years. Because gastrointestinal side effects were the most prominent side effect category, these observations suggest that gastrointestinal tolerance of phytoestrogen supplements is reduced in older women and in Asian women whose diet is characterized by a high underlying consumption of phytoestrogens. We also investigated whether the duration of phytoestrogen supplementation affected the risk of side effects. When using various study duration cut points such as 6, 12, and 24 months, we did not observe an association between study duration and a higher rate of side effects. To the contrary, side effects were observed less often in women using phytoestrogens for a longer period of time. These observations are somewhat reassuring, indicating that there are no cumulative dose effects of phytoestrogens over time. Our study has strengths and weaknesses. For example, the method of meta-analysis reduces the likelihood of chance findings and inter-study variation based on ethnicity or treatment differences. Also, the large number of studies and study participants allows for the identification of side effects with small effect sizes and time-dependent trends towards changing rates of side effects with increasing study duration. On the other hand, we pooled the data of various phytoestrogen compounds, thus potentially masking the existence of different phytoestrogen-specific side effect profiles. Also, the median study duration of the investigated studies was 6.2 months, reflecting the fact that most of the published randomized controlled trials were of limited duration. Thus, we cannot rule out that rare side effects may occur in women on long-term treatment with phytoestrogens. This has to be acknowledged when interpreting the results of this study. Based on the available data, however, the use of phytoestrogens over a period of 2 years can be recommended. In individual studies, a statistically significant difference in the incidence of side effects between the phytoestrogen and control groups was reported in 2/92 randomized controlled trials. One study reported a higher rate of endometrial hyperplasia without atypia after 5 years of phytoestrogen supplementation. This finding was never confirmed in another study. Thus, it cannot be ruled out that long-term treatment may be associated with an increased risk of endometrial hyperplasia without atypia. However, there was no increased risk of endometrial or breast cancer in any individual study, as well as the meta-analysis of all studies. Our findings have implications for women seeking safe treatment alternatives to hormone replacement therapy. Based on our findings, they can be assured that there is no indication of serious unwanted side effects of phytoestrogen treatment such as those found in women on hormone replacement therpy, for example, thrombosis, myocardial infarction, stroke, and breast cancer. It has to be acknowledged, however, that our study does not make any statement about the efficacy of phytoestrogen treatment, which has been discussed controversially.99 In summary, we found that phytoestrogen supplements have a safe side-effect profile with moderately elevated rates of gastrointestinal side effects, abdominal pain, myalgia, and sleepiness. Use of phytoestrogens is not associated with an increased risk of endometrial cancer or breast cancer. Acknowledgements Clemens Tempfer had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. References 1. 1Kronenberg F, Fugh-Berman A. Complementary and alternative medicine for menopausal symptoms: a review of randomized, controlled trials. Ann Intern Med. 2002;137:805–813. 2. 2Albertazzi P, Purdie D. The nature and utility of the phytoestrogens: a review of the evidence. Maturitas. 2002;42:173–185. Abstract | Full Text |
Full-Text PDF (182 KB)
|
CrossRef
3. 3Ju YH, Doerge DR, Allred KF, et al. Dietary genistein negates the inhibitory effect of tamoxifen on growth of estrogen-dependent human breast cancer (MCF-7) cells implanted in athymic mice. Cancer Res. 2002;62:2474–2477. MEDLINE 4. 4Ju YH, Doerge DR, Woodling KA, et al. Dietary genistein negates the inhibitory effect of letrozole on the growth of aromatase-expressing estrogen-dependent human breast cancer cells (MCF-7Ca) In Vivo. Carcinogenesis. 2008;29:2162–2168.
CrossRef
5. 5Wagner J, Jiang L, Lehmann L. Phytoestrogens modulate the expression of 17alpha-estradiol metabolizing enzymes in cultured MCF-7 cells. Adv Exp Med Biol. 2008;617:625–632.
CrossRef
6. 6Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Series B Stat Methodol. 1995;57:289–300. 7. 7Albertazzi P, Steel SA, Bottazzi M. Effect of pure genistein on bone markers and hot flushes. Climacteric. 2005;8:371–379. MEDLINE |
CrossRef
8. 8Albertazzi P, Pansini F, Bonaccorsi G, et al. The effect of dietary soy supplementation on hot flushes. Obstet Gynecol. 1998;91:6–11. MEDLINE |
CrossRef
9. 9Allen JK, Becker DM, Kwiterovich PO, et al. Effect of soy protein-containing isoflavones on lipoproteins in postmenopausal women. Menopause. 2007;14:106–114. MEDLINE |
CrossRef
10. 10Arjmandi BH, Lucas EA, Khalil DA, et al. One year soy protein supplementation has positive effects on bone formation markers but not bone density in postmenopausal women. Nutr J. 2005;4:8. MEDLINE |
CrossRef
11. 11Arjmandi BH, Khalil DA, Smith BJ, et al. Soy protein has a greater effect on bone in postmenopausal women not on hormone replacement therapy, as evidenced by reducing bone resorption and urinary calcium excretion. J Clin Endocrinol Metab. 2003;88:1048–1054.
CrossRef
12. 12Atkinson C, Oosthuizen W, Scollen S, et al. Modest protective effects of isoflavones from a red clover-derived dietary supplement on cardiovascular disease risk factors in perimenopausal women, and evidence of an interaction with ApoE genotype in 49-65 year-old women. J Nutr. 2004;134:1759–1764. MEDLINE 13. 13Atteritano M, Marini H, Minutoli L, et al. Effects of the phytoestrogen genistein on some predictors of cardiovascular risk in osteopenic, postmenopausal women: a two-year randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2007;92:3068–3075.
CrossRef
14. 14Aubertin-Leheudre M, Lord C, Khalil A, Dionne IJ. Six months of isoflavone supplement increases fat-free mass in obese-sarcopenic postmenopausal women: a randomized double-blind controlled trial. Eur J Clin Nutr. 2007;61:1442–1444.
CrossRef
15. 15Balk JL, Whiteside DA, Naus G, et al. A pilot study of the effects of phytoestrogen supplementation on the postmenopausal endometrium. J Soc Gynecol Investig. 2002;9:238–242. MEDLINE |
CrossRef
16. 16Blum A, Lang N, Peleg A, et al. Effects of oral soy protein on markers of inflammation in postmenopausal women with mild hypercholesterolemia. Am Heart J. 2003;145(2):e7. Abstract | Full Text |
Full-Text PDF (74 KB)
|
CrossRef
17. 17Brink E, Coxam V, Robins S, et al.PHYTOS Investigators Long-term consumption of isoflavone-enriched foods does not affect bone mineral density, bone metabolism, or hormonal status in early postmenopausal women: a randomized, double-blind, placebo controlled study. Am J Clin Nutr. 2008;87:761–770. 18. 18Burke BE, Olson RD, Cusack BJ. Randomized, controlled trial of phytoestrogen in the prophylactic treatment of menstrual migraine. Biomed Pharmacother. 2002;56:283–288. MEDLINE |
CrossRef
19. 19Campagnoli C, Abba C, Ambroggio S, et al. Polyunsaturated fatty acids (PUFAs) might reduce hot flushes: an indication from two controlled trials on soy isoflavones alone and with a PUFA supplement. Maturitas. 2005;51:127–134. Abstract | Full Text |
Full-Text PDF (156 KB)
|
CrossRef
20. 20Cancellieri F, De Leo V, Genazzani AD, 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;56:249–256. Abstract | Full Text |
Full-Text PDF (194 KB)
|
CrossRef
21. 21Casini ML, Marelli G, Papaleo E, et al. Psychological assessment of the effects of treatment with phytoestrogens on postmenopausal women: a randomized, double-blind, crossover, placebo-controlled study. Fertil Steril. 2006;85:972–978. Abstract | Full Text |
Full-Text PDF (114 KB)
|
CrossRef
22. 22Chen YM, Ho SC, Lam SS, et al. Soy isoflavones have a favorable effect on bone loss in Chinese postmenopausal women with lower bone mass: a double-blind, randomized, controlled trial. J Clin Endocrinol Metab. 2003;88:4740–4747.
CrossRef
23. 23Chiechi LM, Secreto G, D'Amore M, et al. Efficacy of a soy rich diet in preventing postmenopausal osteoporosis: the Menfis randomized trial. Maturitas. 2002;42(4):295–300. Abstract | Full Text |
Full-Text PDF (106 KB)
|
CrossRef
24. 24Colacurci N, Chiàntera A, Fornaro F, et al. Effects of soy isoflavones on endothelial function in healthy postmenopausal women. Menopause. 2005;12:299–307. MEDLINE |
CrossRef
25. 25D'Anna R, Baviera G, Corrado F, et al. The effect of the phytoestrogen genistein and hormone replacement therapy on homocysteine and C-reactive protein level in postmenopausal women. Acta Obstet Gynecol Scand. 2005;84:474–477. MEDLINE |
CrossRef
26. 26Davis SR, Briganti EM, Chen RQ, et al. The effects of Chinese medicinal herbs on postmenopausal vasomotor symptoms of Australian women (A randomised controlled trial). Med J Aust. 2001;174:68–71. 27. 27Dodin S, Lemay A, Jacques H, et al. 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. J Clin Endocrinol Metab. 2005;90:1390–1397.
CrossRef
28. 28Faure ED, Chantre P, Mares P. Effects of a standardized soy extract on hot flushes: a multicenter, double-blind, randomised placebo-controlled study. Menopause. 2002;9:329–334. MEDLINE |
CrossRef
29. 29Frei-Kleiner S, Schaffner W, Rahlfs VW, et al. Cimicifuga racemosa dried ethanolic extract in menopausal disorders: a double-blind placebo-controlled clinical trial. Maturitas. 2005;51:397–404. Abstract | Full Text |
Full-Text PDF (197 KB)
|
CrossRef
30. 30Gallagher JC, Satpathy R, Rafferty K, Haynatzka V. The effect of soy protein isolate on bone metabolism. Menopause. 2004;11:290–298. MEDLINE |
CrossRef
31. 31Gardner CD, Newell KA, Cherin R, Haskell WL. The effect of soy protein with or without isoflavones relative to milk protein on plasma lipids in hypercholesterolemic postmenopausal women. Am J Clin Nutr. 2001;73:728–735. MEDLINE 32. 32Garrido A, De la Maza MP, Hirsch S, Valladares L. Soy isoflavones affect platelet thromboxane A2 receptor density but not plasma lipids in menopausal women. Maturitas. 2006;54:270–276. Abstract | Full Text |
Full-Text PDF (115 KB)
|
CrossRef
33. 33González S, Jayagopal V, Kilpatrick ES, et al. Effects of isoflavone dietary supplementation on cardiovascular risk factors in type 2 diabetes. Diabetes Care. 2007;30:1871–1873.
CrossRef
34. 34Hale G, Paul-Labrador M, Dwyer JH, Merz CN. Isoflavone supplementation and endothelial function in menopausal women. Clin Endocrinol (Oxf). 2002;56:693–701. MEDLINE |
CrossRef
35. 35Hallund J, Tetens I, Bügel S, et al. Daily consumption for six weeks of a lignan complex isolated from flaxseed does not affect endothelial function in healthy postmenopausal women. J Nutr. 2006;136:2314–2318. MEDLINE 36. 36Han KK, Soares JM, Haidar MA, et al. Benefits of soy isoflavone therapeutic regimen on menopausal symptoms. Obstet Gynecol. 2002;99:389–394. MEDLINE |
CrossRef
37. 37Harkness LS, Fiedler K, Sehgal AR, et al. Decreased bone resorption with soy isoflavone supplementation in postmenopausal women. J Womens Health (Larchmt). 2004;13:1000–1007. MEDLINE 38. 38Heyerick A, Vervarcke S, Depypere H, et al. A first prospective, randomized, double-blind, placebo-controlled study on the use of a standardized hop extract to alleviate menopausal discomforts. Maturitas. 2006;54:164–175. Abstract | Full Text |
Full-Text PDF (419 KB)
|
CrossRef
39. 39Hidalgo LA, Chedraui PA, Morocho N, et al. The effect of red clover isoflavones on menopausal symptoms, lipids and vaginal cytology in menopausal women: a randomized, doubleblind, placebo-controlled study. Gynecol Endocrinol. 2005;21:257–264. MEDLINE |
CrossRef
40. 40Hirata JD, Swiersz LM, Zell B, et al. Does dong quai have estrogenic effects in postmenopausal women? (A double-blind, placebo-controlled trial). Fertil Steril. 1997;68:981–986. Abstract |
Full-Text PDF (716 KB)
|
CrossRef
41. 41Ho SC, Chan AS, Ho YP, et al. Effects of soy isoflavone supplementation on cognitive function in Chinese postmenopausal women: a double-blind, randomized, controlled trial. Menopause. 2007;14(3 Pt 1):489–499. MEDLINE |
CrossRef
42. 42Ho SC, Chen YM, Ho SS, Woo JL. Soy isoflavone supplementation and fasting serum glucose and lipid profile among postmenopausal Chinese women: a double-blind, randomized, placebo-controlled trial. Menopause. 2007;14:905–912.
CrossRef
43. 43Howes JB, Bray K, Lorenz L, et al. The effects of dietary supplementation with isoflavones from red clover on cognitive function in postmenopausal women. Climacteric. 2004;7:70–77. MEDLINE |
CrossRef
44. 44Izumi T, Saito M, Obata A, et al. Oral intake of soy isoflavone aglycone improves the aged skin of adult women. J Nutr Sci Vitaminol (Tokyo). 2007;53:57–62. MEDLINE |
CrossRef
45. 45Jacobson JS, Troxel AB, Evans J, et al. Randomized trial of black cohosh for the treatment of hot flashes among women with a history of breast cancer. J Clin Oncol. 2001;19:2739–2745. 46. 46Jayagopal V, Albertazzi P, Kilpatrick ES, et al. Beneficial effects of soy phytoestrogen intake in postmenopausal women with type 2 diabetes. Diabetes Care. 2002;25:1709–1714. MEDLINE |
CrossRef
47. 47Katz DL, Evans MA, Njike VY, et al. Raloxifene, soy phytoestrogens and endothelial function in postmenopausal women. Climacteric. 2007;10:500–507.
CrossRef
48. 48Khaodhiar L, Ricciotti HA, Li L, et al. Daidzein-rich isoflavone aglycones are potentially effective in reducing hot flashes in menopausal women. Menopause. 2008;15:125–132. 49. 49Knight DC, Howes JB, Eden JA, Howes LG. Effects on menopausal symptoms and acceptability of isoflavone-containing soy powder dietary supplementation. Climacteric. 2001;4:13–18. MEDLINE |
CrossRef
50. 50Kotsopoulos D, Dalais FS, Liang Y-L, et al. The effects of soy protein containing phytoestrogens on menopausal symptoms in postmenopausal women. Climacteric. 2000;3:161–167. MEDLINE |
CrossRef
51. 51Kreijkamp-Kaspers S, Kok L, Grobbee DE, 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;292:65–74.
CrossRef
52. 52Kumar NB, Cantor A, Allen K, et al. The specific role of isoflavones on estrogen metabolism in premenopausal women. Cancer. 2002;94:1166–1174. 53. 53Lampe JW, Skor HE, Li S, et al. Wheat bran and soy protein feeding do not alter urinary excretion of the isoflavan equol in premenopausal women. J Nutr. 2001;131:740–744. MEDLINE 54. 54Lewis JE, Nickell LA, Thompson LU, et al. A randomized controlled trial of the effect of dietary soy and flaxseed muffins on quality of life and hot flashes during menopause. Menopause. 2006;13:631–642. MEDLINE |
CrossRef
55. 55Lucas EA, Wild RD, Hammond LJ, et al. Flaxseed improves lipid profile without altering biomarkers of bone metabolism in postmenopausal women. J Clin Endocrinol Metab. 2002;87:1527–1532.
CrossRef
56. 56Lydeking-Olsen E, Beck-Jensen JE, Setchell KD, Holm-Jensen T. Soymilk or progesterone for prevention of bone loss—a 2 year randomized, placebo-controlled trial. Eur J Nutr. 2004;43:246–257. MEDLINE |
CrossRef
57. 57MacGregor CA, Canney PA, Patterson G, et al. A randomised double-blind controlled trial of oral soy supplements versus placebo for treatment of menopausal symptoms in patients with early breast cancer. Eur J Cancer. 2005;41:708–714. Abstract | Full Text |
Full-Text PDF (126 KB)
|
CrossRef
58. 58Maesta N, Nahas EA, Nahas-Neto J, et al. Effects of soy protein and resistance exercise on body composition and blood lipids in postmenopausal women. Maturitas. 2007;56:350–358. Abstract | Full Text |
Full-Text PDF (143 KB)
|
CrossRef
59. 59Martini MC, Dancisak BB, Haggans CJ, et al. Effects of soy intake on sex hormone metabolism in premenopausal women. Nutr Cancer. 1999;34:133–139. MEDLINE |
CrossRef
60. 60Maskarinec G, Takata Y, Franke AA, et al. A 2-year soy intervention in premenopausal women does not change mammographic densities. J Nutr. 2004;134:3089–3094. MEDLINE 61. 61Maskarinec G, Williams AE, Inouye JS, et al. A randomized isoflavone intervention among premenopausal women. Cancer Epidemiol Biomarkers Prev. 2002;11:195–201. MEDLINE 62. 62Morabito N, Crisafulli A, Vergara C, et al. Effects of genistein and hormone-replacement therapy on bone loss in early postmenopausal women: a randomized double-blind placebo-controlled study. J Bone Miner Res. 2002;17:1904–1912. MEDLINE |
CrossRef
63. 63Nahas EP, Neto JN, de Luca L, et al. Benefits of soy germ isoflavones in postmenopausal women with contraindication for conventional hormone replacement therapy. Maturitas. 2004;48:372–380. Abstract | Full Text |
Full-Text PDF (174 KB)
|
CrossRef
64. 64Nahas EA, Nahas-Neto J, Orsatti FL, et al. Efficacy and safety of a soy isoflavone extract in postmenopausal women: a randomized, double-blind, and placebo-controlled study. Maturitas. 2007;58:249–258. Abstract | Full Text |
Full-Text PDF (178 KB)
65. 65Newton KM, Reed SD, LaCroix AZ, et al. Treatment of vasomotor symptoms of menopause with black cohosh, multibotanicals, soy, hormone therapy or placebo. Ann Intern Med. 2006;145:869–879. 66. 66Nikander E, Kilkkinen A, Metsä-Heikkilä M, et al. A randomized placebo-controlled crossover trial with phytoestrogens in treatment of menopause in breast cancer patients. Obstet Gynecol. 2003;101:1213–1220. MEDLINE |
CrossRef
67. 67Osmers R, Friede M, Liske E, et al. Efficacy and safety of isopropanolic black cohosh extract for climacteric symptoms. Obstet Gynecol. 2005;105(5 Pt 1):1074–1083. MEDLINE 68. 68Penotti M, Fabio E, Modena AB, et al. Effect of soy-derived isoflavones on hot flushes, endometrial thickness and the pulsatility index of the uterine and cerebral arteries. Fertil Steril. 2003;79:1112–1117. Abstract | Full Text |
Full-Text PDF (91 KB)
|
CrossRef
69. 69Pockaj BA, Gallagher JG, Loprinzi CL, et al. Phase III double-blind, randomized, placebo-controlled crossover trial of black cohosh in the management of hot flashes: NCCTG Trial N01CC1. J Clin Oncol. 2006;24:2836–2841.
CrossRef
70. 70Quella SK, Loprinzi CL, Barton DL, et al. Evaluation of soy phytoestrogens for the treatment of hot flashes in breast cancer survivors: a North Central Cancer Treatment trial. J Clin Oncol. 2000;18:1068–1074. 71. 71Rad M, Hümpel M, Schaefer O, et al. Pharmacokinetics and systemic endocrine effects of the phyto-oestrogen 8-prenylnaringenin after single oral doses to postmenopausal women. Br J Clin Pharmacol. 2006;62:288–296. MEDLINE |
CrossRef
72. 72Reimann M, Dierkes J, Carlsohn A, et al. Consumption of soy isoflavones does not affect plasma total homocysteine or asymmetric dimethylarginine concentrations in healthy postmenopausal women. J Nutr. 2006;136:100–105. MEDLINE 73. 73Ritchie MR, Morton MS, Thompson AM, et al. Investigation of the reliability of 24 h urine excretion as a biomarker of isoflavone exposure over time and over a wide range of isoflavone intakes. Eur J Clin Nutr. 2004;58:1286–1289. MEDLINE |
CrossRef
74. 74Russo R, Corosu R. The clinical use of a preparation based on phytoestrogens in the treatment of menopausal disorders. Acta Biomed. 2003;74:137–143. MEDLINE 75. 75Samman S, Lyons Wall PM, Chan GS, et al. The effect of supplementation with isoflavones on plasma lipids and oxidisability of low density lipoprotein in premenopausal women. Atherosclerosis. 1999;147:277–283. Abstract | Full Text |
Full-Text PDF (89 KB)
|
CrossRef
76. 76Sammartino A, Di Carlo C, Mandato VD, et al. Effects of genistein on the endometrium: ultrasonographic evaluation. Gynecol Endocrinol. 2003;17:45–49. MEDLINE |
CrossRef
77. 77Sammartino A, Tommaselli GA, Gargano V, et al. 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. Gynecol Endocrinol. 2006;22:646–650. MEDLINE |
CrossRef
78. 78Schult TM, Ensrud KE, Blackwell T, et al. Effect of isoflavones on lipids and bone turnover markers in menopausal women. Maturitas. 2004;48:209–218. Abstract | Full Text |
Full-Text PDF (99 KB)
|
CrossRef
79. 79Secreto G, Chiechi LM, Amadori A, et al. Soy isoflavones and melatonin for the relief of climacteric symptoms: a multicenter, double blind, randomized study. Maturitas. 2004;47:11–20. Abstract | Full Text |
Full-Text PDF (131 KB)
|
CrossRef
80. 80Simons LA, von Konigsmark M, Simons J, Celermajer DS. Phytoestrogens do not influence lipoprotein levels or endothelial function in healthy, postmenopausal women. Am J Cardiol. 2000;85:1297–1301. Abstract | Full Text |
Full-Text PDF (110 KB)
|
CrossRef
81. 81Sites CK, Cooper BC, Toth MJ, et al. Effect of a daily supplement of soy protein on body composition and insulin secretion in postmenopausal women. Fertil Steril. 2007;88:1609–1617. Abstract | Full Text |
Full-Text PDF (554 KB)
|
CrossRef
82. 82Squadrito F, Altavilla D, Crisafulli A, et al. Effect of genistein on endothelial function in postmenopausal women: a randomized, double-blind, controlled study. Am J Med. 2003;114:470–476. Abstract | Full Text |
Full-Text PDF (124 KB)
|
CrossRef
83. 83Squadrito F, Altavilla D, Morabito N, et al. The effect of the phytoestrogen genistein on plasma nitric oxide concentrations, endothelin-1 levels and endothelium dependent vasodilation in postmenopausal women. Atherosclerosis. 2002;163:339–347. Abstract | Full Text |
Full-Text PDF (197 KB)
|
CrossRef
84. 84St 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. 2001;8:17–26. MEDLINE |
CrossRef
85. 85Steinberg FM, Guthrie NL, Villablanca AC, et al. Soy protein with isoflavones has favorable effects on endothelial function that are independent of lipid and antioxidant effects in healthy postmenopausal women. Am J Clin Nutr. 2003;78:123–130. MEDLINE 86. 86Uesugi T, Fukui Y, Yamori Y. Beneficial effects of soybean isoflavone supplementation on bone metabolism and serum lipids in postmenopausal japanese women: a four-week study. J Am Coll Nutr. 2002;21:97–102. MEDLINE 87. 87Unfer V, Casini ML, Costabile L, et al. Endometrial effects of long-term treatment with phytoestrogens: a randomized double-blind placebo-controlled study. Fertil Steril. 2004;82:145–148. Abstract | Full Text |
Full-Text PDF (66 KB)
|
CrossRef
88. 88Upmalis DH, Lobo R, Bradley L, et al. Vasomotor symptom relief by soy isoflavone extract tablets in postmenopausal women: a multicenter double-blind randomized placebo-controlled study. Menopause. 2000;7:236–242. MEDLINE |
CrossRef
89. 89van de Weijer PHM, Barentsen R. Isoflavones from red clover (Promensil) significantly reduce menopausal hot flush symptoms compared with placebo. Maturitas. 2002;42:187–193. Abstract | Full Text |
Full-Text PDF (134 KB)
|
CrossRef
90. 90van 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. J Clin Oncol. 2002;20:1449–1455.
CrossRef
91. 91Verhoeven MO, van der Mooren MJ, van de Weijer PHM, et al. 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;12:412–420. MEDLINE |
CrossRef
92. 92Vigna GB, Pansini F, Bonaccorsi G, et al. Plasma lipoproteins in soy-treated postmenopausal women: a double-blind, placebo-controlled trial. Nutr Metab Cardiovasc Dis. 2000;10:315–322. MEDLINE 93. 93Wiklund IK, Mattsson LA, Lindgren R, Limoni C. Effects of a standardized ginseng extract on quality of life and physiological parameters in symptomatic postmenopausal women: a double-blind, placebo-controlled trial (Swedish Alternative Medicine Group). Int J Clin Pharmacol Res. 1999;19:89–99. MEDLINE 94. 94Wu J, Oka J, Higuchi M, et al. Cooperative effects of isoflavones and exercise on bone and lipid metabolism in postmenopausal Japanese women: a randomized placebo-controlled trial. Metabolism. 2006;55:423–433. Abstract | Full Text |
Full-Text PDF (322 KB)
95. 95Xu X, Harris KS, Wang HJ, et al. Bioavailability of soybean isoflavones depends upon gut microflora in women. J Nutr. 1995;125:2307–2315. MEDLINE 96. 96Xu X, Wang HJ, Murphy PA, Hendrich S. Neither background diet nor type of soy food affects short-term isoflavone bioavailability in women. J Nutr. 2000;130:798–801. MEDLINE 97. 97Ye YB, Tang XY, Verbruggen MA, Su YX. Soy isoflavones attenuate bone loss in early postmenopausal Chinese women: a single-blind randomized, placebo-controlled trial. Eur J Nutr. 2006;45:327–334. MEDLINE |
CrossRef
98. 98Zhang G, Qin L, Shi Y. Epimedium-derived phytoestrogen flavonoids exert beneficial effect on preventing bone loss in late postmenopausal women: a 24-month randomized, double-blind and placebo-controlled trial. J Bone Miner Res. 2007;22:1072–1089. MEDLINE |
CrossRef
99. 99Tempfer CB, Bentz EK, Leodolter S, et al. Phytoestrogens in clinical practice: a review of the literature. Fertil Steril. 2007;87:1243–1249. Abstract | Full Text |
Full-Text PDF (130 KB)
|
CrossRef
a Department of Obstetrics and Gynecology, Medical University Vienna, Austria b Department of Medical Statistics, Medical University Vienna, Austria  Requests for reprints should be addressed to Clemens Tempfer, MD, Department of Obstetrics & Gynecology; Medical University Vienna, Waehringer Guertel 18-20, A-1090 Vienna/Austria
Conflict of Interest: Authors CBT and JCH received lecture fees by Apomedica Inc. All other authors report no conflict of interest. Authorship: All authors had access to the data and a role in writing the manuscript. PII: S0002-9343(09)00542-7 doi:10.1016/j.amjmed.2009.04.018 © 2009 Elsevier Inc. All rights reserved. | |
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