Introduction: In breast cancer patients, menopausal symptoms are often reached earlier and in a more severe manner than in healthy women. They can dramatically reduce a patient’s quality of life. Treatment for breast cancer patients remains difficult due to hormone replacement therapy being contraindicated. Therefore, treatment alternatives like herbal phytoestrogen preparations are considered to be a treatment option. Methods: All randomized controlled trials (RCTs) that investigated comparisons of food products, extracts, or dietary supplements containing phytoestrogens in women with a diagnosis of breast cancer were included in the analysis. Results: There was no evidence that phytoestrogen preparations had a benefit over placebo in the treatment of breast cancer patients with menopausal symptoms. Neither the frequency nor severity of menopausal symptoms and the quality of life or occurrence of adverse events were reduced in comparison to a placebo. Conclusion: As we cannot prove a benefit of plant extracts in the treatment of menopausal symptoms in breast cancer patients, different herbal preparations should be analyzed in RCTs in order to find sufficient and safe new treatment options for symptomatic menopausal breast cancer patients. A focus should also be laid on developing a core outcome set to simplify pooling of different studies.

Menopause is defined as the end of a woman’s natural reproductive period and usually occurs when the last menstrual period has been absent for 12 months [1]. Particularly in early and late menopause and early postmenopause, the dramatic hormonal shift can lead to vasomotor and vulvovaginal atrophic symptoms (i.e., vaginal atrophy and vaginal dryness), mood disorders, depression, sexual dysfunction, and insomnia in up to four out of five women [2]. In addition, perimenopause may also be associated with a decline in quality of life [3].

Studies show that approximately 9.3 million women worldwide have had a breast cancer diagnosis [4]. Next to reaching menopause earlier, patients also experience aggravated symptoms compared to healthy women. A prospective study showed that one in two of 41 former breast cancer patients had hot flashes – whereas only one in five of the 57 women without cancer were suffering from menopausal vasomotor symptoms [5].

It is especially two groups of breast cancer patients who suffer from menopausal symptoms. First, the cessation of a woman’s hormone therapy that is due to a new breast cancer diagnosis can lead to menopausal symptoms. Second, breast cancer patients who are being treated with systemic therapy often experience menopausal symptoms as therapy side effects.

When asked about the prevalence and severity of menopausal symptoms, breast cancer survivors who have taken tamoxifen have reported that more than half of them were suffering from night sweats and more than three-quarters were experiencing hot flashes [6]. Moreover, tamoxifen treatment is also closely linked to a higher prevalence of sleeping difficulties and depression [7]. It is currently not possible to foresee whether menopausal symptoms will be of short or long duration. However, the older patients are more likely to suffer from permanent menopausal symptoms [8].

Even though endocrine therapy reduces the recurrence rate of breast cancer, studies show that 8–73% of treated breast cancer patients think about stopping their endocrine therapy since the experienced side effects have such a strong impact on their life [9, 10]. Since breast cancer patients are advised to take endocrine therapy for up to 10 years, side effects, as well as possible treatment-associated morbidity, should be taken seriously especially since the patient’s compliance is greatly associated with the quality of life of patients [10].

Treatment Options in Menopausal Breast Cancer Patients

The most common treatment in women who experience menopausal symptoms is hormone therapy (MHT) [11]. However, this is not recommended for survivors of breast and endometrial cancer, especially when the cancer is estrogen-sensitive [1]. It is therefore important that treatment options for menopausal symptoms, which are safer and less costly than MHT, but comparatively effective, are identified so that the impact of climacteric symptoms on perimenopausal women can be attenuated and quality of life improved.

Phytoestrogens as a Treatment Option for Breast Cancer Patients

Herbal preparations are popular with many women in menopause. Black cohosh, red clover, or St. John’s wort alleviated hot flashes in many studies. However, there is still a lack of large studies that investigate the use of herbals in breast cancer patients.

Dietary phytoestrogens have been primarily studied because cultures whose diet consists of a high amount of these substances have oftentimes a lower incidence of menopausal symptoms than other countries. Phytoestrogens are nonsteroidal compounds that exhibit similarities to 17-beta-estradiol [12]. The most common groups of phytoestrogens are isoflavones, coumestans, stilbenes, and lignans. Two important isoflavones are genistein and daidzein [12]. While soy contains a high amount of isoflavones, flaxseed mostly contains lignans. Phytoestrogens can both express estrogenic and antiestrogenic activity [13]. Until today, however, it is not yet clear whether phytoestrogen supplements are a safe option for patients after a breast cancer diagnosis [14].

To investigate phytoestrogen treatment in breast cancer patients, we included all randomized controlled trials (RCTs) that investigated comparisons of food products, extracts, or dietary supplements containing phytoestrogens in women with a diagnosis of breast cancer in the analysis. Databases such as Cochrane, MEDLINE, Embase, trial registries, and other sources were searched systematically up to December 2021. Our primary outcomes were menopausal symptoms and incidence and type of adverse events. Our secondary outcomes were quality of life and the acceptability of therapy. Two review authors independently selected trials, extracted the data, and assessed trial quality.

We screened 3,744 abstracts and 505 full-text studies. A total of 4 RCTs (306 women) met the inclusion criteria and were included in our analysis [15‒18]. Women had to have a preexisting breast cancer diagnosis and experience baseline menopausal symptoms if they were to be included in our analysis. In all the studies, phytoestrogen treatment was compared to the placebo. Three studies used soy [15, 17, 18], and one used red clover as a source of isoflavones in their comparison [16].

All studies used either menopausal symptom diaries to evaluate the hot flush frequency and severity or standardized questionnaires like the Kupperman index or menopausal rating scale to assess vasomotor symptoms. One study looked at the patient’s quality of life [15]. Two studies evaluated adverse events [15, 18].

Vasomotor Symptoms

All studies used different symptom scores to evaluate the incidence, severity, and frequency of vasomotor symptoms. We were, therefore, not able to do a pooled analysis. Different scores and results have been summarized in Table 1. In a nutshell, results have been reported as follows:

Table 1.

The following studies compared vasomotor symptoms in breast cancer patients

 The following studies compared vasomotor symptoms in breast cancer patients
 The following studies compared vasomotor symptoms in breast cancer patients

• Nikander et al. [17]: Even though phytoestrogen treatment reduced the Kupperman index by 4.2%, the reduction was comparable in the placebo treatment arm. Likewise, the severity of menopausal symptoms assessed through a visual analogue scale also did not differ between phytoestrogen and placebo treatment: it ranged from 8 to 89 mm before the trial, from 1 to 100 mm after phytoestrogen treatment, and from 3 to 100 mm (49.323.1) after the placebo regimen [18].

• Ferraris et al. [16]: The menopausal rating scale was reduced by at least 2 points in 92.9% of the treatment and 97.4% of the placebo patients. Also, the number of reported symptoms decreased in both groups.

• Quella et al. [18]: 26% of patients receiving soy treatment reported that their hot flash frequency was cut in half compared to 36% of patients that received placebo treatment.

Adverse Events

Two of the studies reported adverse events as one of their main outcomes. Both concluded that there was only mild toxicity. MacGregor et al. [15] indicated that patients did, indeed, experience gastrointestinal symptoms, which, however, was also measured in the placebo arm. Quella et al. [18] also did not find any differences concerning mild adverse events like diarrhea, nausea, vomiting, or bloating/gas (Table 2).

Table 2.

The following studies compared adverse events in breast cancer patients

 The following studies compared adverse events in breast cancer patients
 The following studies compared adverse events in breast cancer patients

Quality of Life

One study reported about quality of life that was measured by using the EORTC global quality of life score. The last recorded global quality of life score was analyzed using ANOVA, but no difference between the placebo or isoflavone arm was found ([treatment placebo-soya] = 3.0 [S.E. = 3.6, p = 0.844]) [15] (Table 3).

Table 3.

The following study analysed quality of life in breast cancer patients

 The following study analysed quality of life in breast cancer patients
 The following study analysed quality of life in breast cancer patients

The current analysis of four randomized controlled clinical trials shows that phytoestrogen treatment has probably no effect on reducing women’s menopausal vasomotor symptoms when compared to placebo treatment. If there was, indeed, a reduction of their symptoms, the effect was also comparable in the placebo arm of the study. There was also no indication that quality of life was any better when patients were treated with isoflavones than compared to a placebo. The assessment of adverse events showed that there is probably only mild toxicity with only mild adverse events compared to placebo treatment.

Since these findings appear in women with a former treatment of breast cancer, comparing the results to meta-analyses in otherwise healthy menopausal women is important, especially because the former intake of anti-hormonal drugs might play a role in mitigating or at least influencing the effect of phytoestrogens [19].

However, comparable meta-analyses investigating vasomotor symptoms in menopausal patients without a breast cancer diagnosis concluded that phytoestrogens do not change the Kupperman’s index as well [20‒22]. It was, nonetheless, observed that phytoestrogens led to a reduction in the frequency of hot flushes in one analysis [20]. This effect, though, probably only leads to a symptom reduction of up to 10% compared to the placebo [21]. When the quality of life was assessed, one of the mentioned meta-analyses observed no improvement [22].

Two comparable meta-analyses in breast cancer patients confirmed our findings: no significant effect could be made out when phytoestrogen and placebo treatment were observed [23, 24]. One of them, however, concluded that phytoestrogens are safe to use and might even lead to a reduction in breast cancer recurrence and mortality, even though the analyzed studies were not uniform about this. The reason behind the observed effect being that phytoestrogens might block proliferative effects of estradiol on cancer cells [24].

In contrast to synthetic female hormones that are used in menopausal patients, botanic estrogens have failed to show an effect in the four studies we examined. The studies that were closely examined did not show any effect on menopausal symptoms or make a difference in the quality of life of breast cancer patients when compared to placebo treatment. These results can be compared to two other meta-analyses that draw similar conclusions [23, 24].

Until today, many trials are still too small, their duration is too short, or the drugs show a lack of effect. Efforts should be put into analyzing more and different herbal preparations. Black cohosh does, for example, not bind to estrogen receptors and does not show the usual estrogenic effects. It might, therefore, be useful to address this drug in breast cancer patients as well. In addition, core outcome sets have been recently established for infertility and pre-eclampsia research. The outcome sets, thereby, simplify the pooling of heterogenous studies and produce more significant results [25, 26].

The best management of menopausal symptoms for patients and their doctors remains a difficult one that needs to be addressed together on an individual basis. Before more impactful studies exist, the risks and benefits of each intervention should be closely looked at before deciding what to do.

• An effect on menopausal symptoms by phytoestrogens in breast cancer patients that goes beyond the placebo effect cannot be assumed at present on the basis of the current study situation.

• The current data on herbal therapy for menopausal symptoms in breast cancer patients are still insufficient. In addition, no core outcome values exist that would facilitate standardization and easier pooling of studies.

The research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. In all used studies, subjects have given their written informed consent, and each study protocol was approved by the institute’s committee on human research.

The authors have no conflicts of interest to declare.

No funding was used.

Marie Vogel, Sebastian Franik, and Ludwig Kiesel have all contributed to the study.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author (Marie Vogel, m_voge26@uni-muenster.de).

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