The American Journal of Medicine
Volume 122, Issue 10 , Pages 939-946.e9, October 2009

Side Effects of Phytoestrogens: A Meta-analysis of Randomized Trials

  • Clemens B. Tempfer, MD

      Affiliations

    • Department of Obstetrics and Gynecology, Medical University Vienna, Austria
    • Corresponding Author InformationRequests for reprints should be addressed to Clemens Tempfer, MD, Department of Obstetrics & Gynecology; Medical University Vienna, Waehringer Guertel 18-20, A-1090 Vienna/Austria
    • ,
  • Georg Froese, MD

      Affiliations

    • Department of Obstetrics and Gynecology, Medical University Vienna, Austria
    • ,
  • Georg Heinze, PhD

      Affiliations

    • Department of Medical Statistics, Medical University Vienna, Austria
    • ,
  • Eva-Katrin Bentz, MD

      Affiliations

    • Department of Obstetrics and Gynecology, Medical University Vienna, Austria
    • ,
  • Lukas A. Hefler, MD

      Affiliations

    • Department of Obstetrics and Gynecology, Medical University Vienna, Austria
    • ,
  • Johannes C. Huber, MD, PhD

      Affiliations

    • Department of Obstetrics and Gynecology, Medical University Vienna, Austria

Article Outline

Abstract 

Background

Phytoestrogens are widely used by postmenopausal women for the treatment of the climacteric syndrome. The risk of adverse effects of this treatment, however, is unknown.

Methods

Using a fixed-effects model, we performed a meta-analysis of side effects comparing phytoestrogen treatment with placebo or no treatment in randomized controlled trials.

Results

We 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.

Conclusions

Based 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.

Keywords: Climacteric syndrome, Hormone replacement, Meta-analysis, Phytoestrogens, Soy

 

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.

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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).

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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.

Table 1. Characteristics of Studies and Participants
First Author (Year of Publication)Participants (Withdrawn)Inclusion CriteriaParticipant CharacteristicsStudy DurationStudy Medication
Albertazzi (2005)7100(1)
Amenorrhea ≥12 mos and ≤10 years;

HRT ex ≥1 year;

No secondary causes of bone loss


MA 53.5 years;

MBMI 27

6wksCapsules (90 mg/d genistein)
Albertazzi (1998)8104(25)
Amenorrhea ≥6 mos or

Oophorectomy ≥6 wks;

≥7 HF/d;

FSH >50 IU/L;

E2 <35 pg/mL

HRT ex ≥6 wks


MA 52.9 years;

MBMI 25.9

12wksSoy protein (76 mg/d isoflavones)
Allen (2007)9216(25)
Amenorrhea ≥12 mos or

FSH >30 IU/L and

LDL 3.37-4.92 nmol/L or

Triglycerides >1.7 nmo/L;


MA 56.8 years;

MBMI 27.94

12wksSoy protein (160 mg/d isoflavones)
Arjmandi (2005)1087(25)
Postmenopausal;

Age <65 years;

No HRT;


MA 54.5 years;

MBMI 27.95

12mosSoy protein (60 mg/d isoflavones)
Arjmandi (2003)1171(29)Postmenopausal
MA 62.1 years;

MBMI 32.2

3mosSoy protein (88.4 mg/d isoflavones)
Atkinson (2004)12205(28)
Age 49-65 years;

Breast density


MA 55.2 years;

MBMI 25.3

12mosPromensil® (Red Clover; 43.5 mg/d isoflavones)
Atteritano (2007)13389(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


MA 54.5 years

MBMI 25

24mosTablets (54 mg/d genisteinisoflavone)
Aubertin-Leheudre (2007)1424(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


MA 58 years

MBMI 29.5

6mosSoy capsules (70 mg/d isoflavones)
Balk (2002)1527(8)
Age >40 years and

Amenorrhea ≥12 mos or

Age >30 years and

Oophorectomy/ovarian failure;

Intact uterus;

Omnivorous


MA 57.4 years

MBMI -

6mosSoy flour (100 mg/d isoflavones)
Blum (2003)1630(6)
Postmenopausal;

Hypercholesterolemia;

HRT ex ≥2 mos;

LDL>130 mg/dL;


MA 55 years

MBMI -

6wksSoy protein (25g/d)
Brink (2008)17300(63)
Amenorrhea 12-60 mos;

FSH >20 IU/L;

Non-osteoporotic;

BMI 22-29 kg/m2;


MA 53 years

MBMI 24.5

12mosSoy protein (110 mg/d isoflavones)
Burke (2002)1849(7)
Age 18-48 years;

Active menstruation;

Non-complex migraine without aura;

Migrain attacks >1 year;

Migrain attacks/mos ≥3


MA 39.5 years

MBMI -

28wksCombination (60 mg/d soy isoflavones; 100 mg/d dong quai; 50 mg/d black cohosh)
Campagnoli (2005)1961(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


MA 51.5 years

MBMI 24.5

12wksSoy capsules (60 mg/d isoflavones±PUFA)
Cancellieri (2007)20142(17)
Postmenopausal;

Age 45-65 years;

No pharmacological treatment <30 d


MA 54.3 years

MBMI 24.9

6mosCombination (Soy extract, red clover and black cohosh; 72 mg/d isoflavones)
Casini (2006)2178(2)
Intact uterus;

Amenorrhea ≥12 mos;

FSH >30 IU/L;

E2 <10 pg/mL;


MA 49.5 years

MBMI 24.6

6mosSoy Protein (60 mg/d isoflavones)
Chen (2003)22203(26)
Age 48-62 years;

Amenorrhea ≥12 mos;


MA 54.2 years

MBMI 24

12mosSoy extract (40 mg/d or 80 mg/d isoflavones)
Chiechi (2002)23187(58)
Amenorrhea ≥6 mos,

FSH >30 IU/L and

E2 <20 pg/mL or

bilateral ovariectomy


MA 53.4 years

MBMI 27.7

6mosSoy protein (47 mg/d isoflavones)
Colacurci (2005)2460(3)
Amenorrhea;

No HRT (ever)


MA 55.2 years

MBMI 25.9

6mosTablets (60 mg/d isoflavones)
D'Anna (2005)2590(9)
Age 50-60 years;

Amenorrhea ≥12 mos;

FSH >50 IU/L


MA -

MBMI -

6mosTablets (54 mg/d genistein isoflavone)
Davis (2001)2678(23)
Non-asian women;

Age 45-70 years;

Lived in Australia ≥10 years;

Amenorrhea ≥12 mos;

FSH >25 IU/L;

≥14 HF/wk


MA 55.2 years

MBMI 25.9

12wksChinese medical herbs
Dodin (2005)27199(43)
Age 45-65 years;

FSH ≥40 IU/L;

Amenorrhea ≥6 mos;

Normal mammogram <2 years;


MA 54.7 years

MBMI 26.2

12mos40 g/d flaxseed
Faure (2002)2875(20)
≥7 HF/d;

FSH >40 IU/L;

E2 <35 pg/mL;

HRT ex ≥6 wks


MA 53.5 years

MBMI 24.9

4mosSoy extract (70 mg/d isoflavones)
Frei-Kleiner (2005)29127(15)
Age 45-60 years;

≥3 HF/d;

≥1 functioning ovary; climacteric disorders


MA 52.4 years

MBMI 24.5

12wksC. racemosa (42 mg/d crude drug)
Gallagher (2004)3065(15)
Amenorrhea ≥12 mos or FSH >35 IU/L and

E2 <30 pg/mL


MA 55.4 years

MBMI 26.4

9mosSoy protein (96 mg/d or 52 mg/d isoflavones)
Gardner (2001)31100(6)
Amenorrhea ≥12 mos;

Age <80 years;

BMI 20-31 kg/m2


MA 59.6 years

MBMI 26

12wksSoy Protein (3 mg/d or 80 mg/d isoflavones)
Garrido (2006)3229(0)
Age 45-60 years;

Amenorrhea ≥6 mos;

FSH >20 IU/L;

HRT ex >6 mos


MA 53.5 years

MBMI 27

12wksSoy protein (100 mg/d isoflavones)
González (2007)3332(6)
NIDDM;

Amenorrhea ≥12 mos


MA -

MBMI 31

12wksSoy protein (132 mg/d isoflavones)
Hale (2002)3432(3)
Age 45-70 years;

Amenorrhea ≥12 mos;

HRT ex ≥6 mos;

≥6 mos no Antibiotics;

≥12 mos no smoking;

BMI <35 kg/m2


MA 57.3 years

MBMI 24.9

2wksSoy protein (80 mg/d isoflavones)
Hallund (2006)3523(1)
Amenorrhea ≥24 mos;

≥6 mos no HRT;

≥3 mos no Antibiotics


MA 61 years

MBMI 24.1

6wksLignan Complex (500 mg/d)
Han (2002)3682(2)
Age 45-55 years;

Amenorrhea ≥12 mos;

≥12 mos no HRT; intact uterus;

FSH >25 IU/L;

E2 <20 pg/mL;

HF


MA 48.5 years

MBMI 24.9

4mos(100 mg/d isoflavones)
Harkness (2004)3720(1)
Amenorrhea >8 years;

Age >50 years;

≥3 mos no HRT


MA 70.6 years

MBMI 25.9

6mosSoy protein (110 mg/d isoflavones)
Heyerick (2006)3867(12)
Age 45-60 years;

Intact uterus;

Amenorrhea ≥12 mos;

≥3 mos no HRT;

2-5 HF/d


MA 52.1 years

MBMI 24.5

12wksHop extract (100 μg/d or 250 μg/d 8-PN)
Hidalgo (2005)3960(7)
Amenorrhea >12 mos;

Age >40 years;

No HRT


MA 51.3 years

MBMI -

90daysRed Clover (80 mg/d isoflavones)
Hirata (1997)4071(10)
Amenorrhea ≥6 mos;

Troublesome night sweats


MA 52.4 years

MBMI 24.4

24wksDong quai extract (4.5 g/d)
Ho (2007)41200(23)
Age 55-75 years;

Amenorrhea ≥5 years;

BMI 18-32 kg/m2;

≥6 mos no HRT


MA 63.4 years

MBMI 24.5

6mosSoy protein (80 mg/d isoflavones)
Ho (2007)42203(29)
Age 48-62 years;

Amenorrhea ≥12 mos

or <10 years


MA 54.2 years

MBMI 24.1

12mosSoy protein (40 mg/d or 80 mg/d isoflavones)
Howes (2004)4330(2)
Age >60 years;

Amenorrhea ≥5 years

no HRT (ever)


MA 68.1 years

MBMI -

6mosRimostil® (Red Clover; 80 mg/d isoflavones)
Izumi (2007)4426(0)Age 35-45 years
MA -

MBMI -

12wksSoy protein (40 mg/d isoflavones)
Jacobson (2001)4585(16)
Age >18 years;

≤2 mos before treated for breast cancer (chemo-/radiotherapy)


MA -

MBMI -

2mosC. racemosa
Jayagopal (2002)4633(1)
NIDDM;

Amenorrhea ≥12 mos


MA 62.5 years

MBMI 32.2

12wksSoy protein (132 mg/d isoflavones)
Katz (2007)4725(3)
Amenorrhea ≥12 mos;

FSH >40 IU/L;

E2 <25 pg/mL non-smoker; normolipidemic


MA 58.5 years

MBMI 27.6

6wksSoy protein (55-65 mg/d isoflavones)
Khaodhiar (2008)48191(44)
Amenorrhea ≥6 mos;

Age 38-60 years;

≥4 HF/d


MA 53.1 years

MBMI 28.5

12wksSoft-gel Capsules (40 mg/d or 60 mg/d isoflavones)
Knight (2001)4924(4)
Amenorrhea ≥6 mos,

FSH >40 IU/L or bilateral oopherectomy;

Age 40-65 years;

≥3 HF/d


MA 53 years

MBMI -

12wksTakeCare® (134.4 mg/d isoflavones, 77.4 mg/d aglycone)
Kotsopoulos (2000)5094(19)
Age 50-75 years;

Amenorrhea ≥12 mos;

FSH >20 IU/L;

≥12 mos no HRT;

≥3 mos no antibiotics; non-smokers; non-vegetarian


MA 59.5 years

MBMI 25.5

3mosSoy protein (118 mg/d isoflavones)
Kreijkamp-Kaspers (2004)51202(49)
Age 60-75 years;

⊥mammogram <1 year;

Amenorrhea


MA 66.6 years

MBMI 26.2

12mosSoy protein (99 mg/d isoflavones)
Kumar (2002)5297(31)Age 25-55 years; BMI <38 kg/m2; no HT
MA 41.9 years

MBMI 24.2

12wksSoy protein (40 mg/d isoflavones)
Lampe (2001)5326(6)
Age 20-40 years;

regular menstrual cyclus;

≥4 mos no antibiotics; no HT


MA 32.1 years

MBMI 23.3

1moSoy protein (110 mg/d isoflavones)
Lewis (2006)5499(11)
Age 45-60 years;

Postmenopausal ≥12 mos and <8 years


MA 53.1 years

MBMI 27

16wksFlaxseed (50 mg/d lignans) or Soy Protein (42 mg/d isoflavones)
Lucas (2002)5558(22)
Postmenopausal;

Age <65 years; no HRT


MA 54.5 years

MBMI 28.9

3mosFlaxseed (40g/d)
Lydeking-Olsen (2004)56107(18)
Amenorrhea ≥12 mos;

Age <75 years;

≥2 years no bone-active medication;

≥3 risk-criteria for osteoporosis;


MA 58.2 years

MBMI 23.9

24mosSoymilk (76 mg/d isoflavones)
MacGregor (2005)5772(25)
Age >18 years;

Histological confirmed pre-existing breast cancer; menopausal symptoms


MA 51 years

MBMI -

12wksSoy capsules (70 mg/d isoflavones)
Maesta (2007)5860(14)
Amenorrhea ≥12 mos;

FSH >40 IU/L;

Age 45-70 years


MA 59.4 years

MBMI 27.3

16wksSoy protein (50 mg/d isoflavones)
Martini (1999)5940(2)
Age 18-40 years;

≥6 mos no antibiotics


MA 26.3 years

MBMI 23

2mosSoy product (38 mg/d isoflavones)
Maskarinec (2004)60220(31)Normal mammogram no OC or HAT; intact uterus
MA 43 years

MBMI 26

24mosSoy protein (50 mg/d isoflavones)
Maskarinec (2002)6134(5)
Age 35-46 years;

⊥mammogram <6 mos;

≥3 mos no OC or HAT;

intact uterus; regular menstrual periods


MA 42.4 years

MBMI -

12mosSoy protein (100 mg/d isoflavones)
Morabito (2002)6290(-)
Age 47-57 years;

Amenorrhea ≥12 mos;

FSH >50 IU/L;

E2 <100 pmol/L


MA 51.7 years

MBMI 23.7

12mosTablets (54 mg/d genistein isoflavone)
Nahas (2004)6350(0)
Amenorrhea ≥12 mos;

FSH >40 IU/L;

HF;

Contraindication or intolerance to HRT


MA 53.3 years

MBMI 29

6mosSoy Germ (60 mg/d isoflavones)
Nahas (2007)6480(4)
Age ≥45 years;

Amenorrhea ≥12 mos;

FSH >40 IU/L;

≥5 HF/d


MA 55.1 years

MBMI 29.1

10mosSoy extract (100 mg/d isoflavones)
Newton (2006)65351(45)
Age 45-55 years;

Amenorrhea ≥12 mos;

FSH >20 IU/L;

≥2 vasomotors symptoms per day


MA 52.2 years

MBMI 28.6

12mosC. racemosa (160 mg/d) or MB+C. racemosa (200 mg/d) or MB+soy
Nikander (2003)6662(6)
Climacteric complaints;

FSH >30 IU/L;

Postmenonpausal


MA 54 years

MBMI 23.6

3mosSoy protein (114 mg/d isoflavones)
Osmers (2005)67304(36)
Amenorrhea ≥12 mos or

Amenorrhea ≥6 mos with FSH ≥50 IU/L;

Age ≥45 years;

Climacteric complaints


MA 53.5 years

MBMI 25.2

12wksRemifemi® (C. racemosa; 2.5 mg/d isopropanolic)
Penotti (2003)6862(13)
Age 45-60 years;

Amenorrhea ≥6 mos;

LDL <160 mg/dL


MA 53.5 years

MBMI 23.2

6mosSoy protein (72 mg/d isoflavones)
Pockaj (2006)69132(33)
≥14 HF/wk;

history or increased risk of breast cancer


MA 66.4 years

MBMI -

4wksC. racemosa (20 mg/d)
Quella (2000)70177(28)
Age >18 years;

History of breast cancer (currently without evidence of residual malignant disease;

≥14 HF/wk;


MA -

MBMI -

4wksSoy protein (50 mg/d isoflavones)
Rad (2006)7124(-)
BMI 19-29 kg/m2;

Age 46-65 years;

Amenorrhea ≥12 mos


MA –

MBMI 24.9

2daysC. racemosa (50 mg/d, 250 mg/d or 750 mg/d 8-PN)
Reimann (2006)7299(10)
Age 45-70 years;

Amenorrhea ≥12 mos;

≥6 mos no HRT;

≥3 mos no antibiotics


MA 59 years

MBMI 24.4

8wksSoy protein (50 mg/d isoflavones)
Ritchie (2004)7315(0)
Age 30-51 years;

Regular menstrual cycle


MA 41 years

MBMI 22.9

6mosSoy protein 35 mg/d isoflavones)
Russo (2003)7450(3)
Age 48-54 years;

Amenorrhea ≥12 mos and ≤3 years;

neg. PAP test;

ET ≤4 mm;

Caucasian race;

Climacteric complaints


MA 53.3 years

MBMI 26.3

3mosFitormil® (32 mg/d isoflavones)
Samman (1999)7521(7)
Age 18-45 years;

Regular menstrual cycle;

no HAT or OC


MA 27.5 years

MBMI 21.3

2mosRed clover (86 mg/d isoflavones)
Sammartino(2003)7670(7)
Amenorrhea ≥12 mos;

FSH >40 IU/L;

E2 <20 pg/mL;

≥7HF/d


MA 51.8 years

MBMI 25.3

12mosFitogen® (36 mg/d isoflavones)
Sammartino (2006)7780(5)
Amenorrhea ≥6 mos and ≤2 years;

FSH >40 IU/L;

≥7 HF/d;

BMI 18-30 kg/m2


MA 50.8 years

MBMI 24.7

3mosSoy germ (60 mg/d isoflavones) andlignans (20 mg/d flaxseed) and C. racemosa (1.25 mg/d)
Schult (2004)78252(6)
Age 45-60 years;

≥35 HF/wk;

Amenorrhea ≥6 mos or bilateral oopherectomy;

FSH ≥30 IU/L


MA 52.3 years

MBMI 26.2

12wksPromensil® (82 mg/d isoflavones) or Rimostil® (57.2 mg/d isoflavones)
Secreto (2004)79262(30)
Amenorrhea ≥6 mos;

Age ≥35 years;

≥3 mos no HRT


MA 52.3 years

MBMI 24.1

3mosSoy (80 mg/d isoflavones) or soy+melatonin or melatonin (3 mg/d)
Simons(2000)8023(3)
Age 50-70 years;

Amenorrhea ≥12 mos;

Non-smoking;

Cholesterol <8 mmol/L;

Triglycerides <3 mmol/L


MA 59 years

MBMI 26.8

8wksSoy protein (80 mg/d isoflavones)
Sites (2007)8118(3)
Amenorrhea ≥12 mos and ≤5 years;

FSH >30 IU/L


MA 55.6 years

MBMI 30.5

3mosSoy protein (160 mg/d isoflavones)
Squadrito (2003)8290(11)
Age 52-60 years;

Amenorrhea ≥12 mos;

No surgical menopause;

FSH >50 IU/L;

E2 ≤100 pmol/L


MA 56.3 years

MBMI -

12mosGenistein (54 mg/d)
Squadrito (2002)8360(0)
Age 52-60 years;

Amenorrhea ≥12 mos;

No surgical menopause;

FSH >50 IU/L;

E2 ≤100 pmol/L


MA 56 years

MBMI -

6mosGenistein (54 mg/d)
St Germain (2001)8480(11)
Amenorrhea ≥12 mos;

≥10 HF/wk;

≥12 mos no HT;

BMI 20-31 kg/m2


MA 50 years

MBMI -

6mosSoy Protein (4.4 mg/d or 80.4 mg/d isoflavones)
Steinberg (2003)8542(14)
Amenorrhea ≥12 mos;

FSH ≥23 IU/L;

≥6 mos no HRT;

BMI <30 kg/m2


MA 54.9 years

MBMI 24.6

6wksSoy protein (2 mg/d or 107 mg/d isoflavones)
Uesugi (2002)8623(0)
Age 40-62 years;

perimenopausal


MA 54.1 years

MBMI 22.7

4wksSoy protein (61.8 mg/d isoflavones)
Unfer (2004)87376(78)
Intact uterus;

Amenorrhea ≥12 mos;

FSH ≥30 IU/L


MA 49.5 years

MBMI 24.6

5yearsSoy protein (150 mg/d isoflavones)
Upmalis (2000)88177(55)
Amenorrhea ≥6 mos;

Age ≥50 years;

FSH ≥30 IU/L;

E2 ≤25 pg/mL;

≥5 vasomotor symptoms/d;

≥60 d no HRT


MA 54.8 years

MBMI -

12wksSoy protein (50 mg/d isoflavones)
Van de Weijer (2002)8942(12)
Age 49-65 years;

Amenorrhea ≥12 mos;

≥12 wks no HT or antibiotics


MA 53.4 years

MBMI 25.6

12wksPromensil® (82 mg/d isoflavones)
Van Patten (2002)90157(34)
Amenorrhea ≥12 mos;

≥4 mos no HRT;

≥10 HF/wk; history of breast cancer (>4 mos since completion of treatment)


MA 55.2 years

MBMI 26.7

12wksSoy protein (90 mg/d isoflavones)
Verhoeven(2005)91124(8)
Amenorrhea ≥6 mos;

FSH >25 IU/L;


MA 53.9 years

MBMI 25.5

12wksSoy extract (50 mg/d isoflavones) andC. racemosa (8 mg/d deoxyacetein) and primrose oil (1500 mg/d)
Vigna (2000)92104(27)
Amenorrhea ≥6 mos or Bilateral oopherectomy ≤6 wks;

>7 HF/d;

FSH >50 IU/L;

E2 <130 pmol/L;

≥6 wks no HT


MA 53.4 years

MBMI 25.9

12wksSoy protein (76 mg/d isoflavones)
Wiklund (1999)93384(5)
Age 45-65 years;

≥2 mos no HRT;

Amenorrhea ≥6 mos


MA 53.5 years

MBMI 25.8

16wksGinsana® (100 mg/d ginseng extract)
Wu (2006)94136(8)
Age 45-60 years;

Amenorrhea ≥12 mos and ≤5 years;

no HRT or antibiotics


MA 54.6 years

MBMI 21.7

24wks75 mg/d isoflavones
Xu (1995)957(0)
Omnivorous;

Good general health


MA -

MBMI 22

3daysSoymilk (3.4 or 6.9 or 10.3 μmol/kg/d isoflavones)
Xu (2000)9618(-)
Omnivorous;

Good gerneral health


MA -

MBMI 21.5

1daySoymilk (0.9 mg/d/kg isoflavones)
Ye (2006)9790(8)
Age 45-60 years;

Amenorrhea ≥12 mos and ≤5 years;

FSH >30 IU/L


MA 52.3 years

MBMI 22.6

6mosSoy protein (84 mg/d or 126 mg/d isoflavones)
Zhang (2007)98100(15)
Amenorrhea 10-18 years;

BMD 0.968-1.014g/cm2 at lumbar spine


MA 63.5 years

MBMI 23.8

24mosEpimedium-derived Phytoestrogen flavonoids (78 mg/d isoflavones)

FSH=follicle-stimulating hormone; E2=estradiol; MA=mean age; HF=hot flashes; HRT=hormone replacement therapy; HT=hormone therapy; BMI=body mass index (kg/m2); MBMI=mean body mass index (kg/m2); LDL=low density lipoprotein; BMD=bone mineral density; PUFA=polyunsaturated fatty acids; NIDDM=non-insulin-dependent diabetes mellitus; 8-PN=8-prenylnaringenin; OC=oral contraceptives; MB=multibotanical.

  • View full-size image.
  • Figure 1. 

    Forest plot showing incidence ratios and 95% confidence intervals of side effects in 92 randomized trials comparing phytoestrogens and placebo/no treatment. Phyto=phytoestrogens.

Table 2. Categories of Adverse Events or Side Effects
Gynecological or Urinary AEs or SEs (%)Gastrointestinal AEs or SEs (%)Musculoskeletal AEs or SEs (%)Neurological or Sensory AEs or SEs (%)Nonspecific or Other AEs or SEs (%)Undefined AEs or SEs (%)
Phytoestrogens (n=5502)153(7.8)353(17.9)156(7.9)121(6.1)377(19.1)813(41.2)
Controls (n=4806)117(6.6)239(13.4)112(6.3)101(5.7)379(21.3)832(46.7)
IRR⁎ (95% CI)0.94(0.74-1.20)1.28(1.08-1.50)1.20(0.94-1.53)0.91(0.70-1.19)0.95(0.88-1.03)0.93(0.77-1.14)
P-value0.6120.0030.1430.4810.1890.451

AEs=adverse events; SEs=side effects;

Percentages in parentheses are given per row.

⁎IRR=incidence rate ratio.

  • View full-size image.
  • Figure 3. 

    Forest plot of incidence ratios of side effects according to different study characteristics. IRR=incidence rate ratio; US=United States of America; EU=European Union.

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.

Table 3. Gynecological and Urinary Adverse Events or Side Effects
Vaginal BleedingVaginal SpottingNipple DischargeBreast Pain, Enlargement or MastodyniaBreast Cancer (Breast Cancer Recurrence)Endometrial HyperplasiaPelvic DiscomfortNycturiaOthers or Undefined
Phytoestrogens (n=5502)48501211(2)141148
Controls (n=4806)291055(0)60048
P-value0.90.4—1.00.9(0.9)0.61.01.01.0
Table 4. Gastrointestinal Adverse Events or Side Effects
ConstipationDiarrheaGastroenteritisBloating or FlatulenceNausea or VomitingAbdominal PainDyspepsiaEpigastric PainOthers or Undefined
Phytoestrogens (n=5502)6977553527127141
Controls (n=4806)57623622940107
P value0.91.00.40.60.20.20.30.20.9

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

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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.

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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.

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 Funding: None.

 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

The American Journal of Medicine
Volume 122, Issue 10 , Pages 939-946.e9, October 2009

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