The Effectiveness of Herbal Medicines on Cyclic Mastalgia: A Systematic Review on Meta-analysis

Objective  Different drugs are used to treat mastalgia, such as danazol and bromocriptine, and both are associated with side effects, due to which most of women and healthcare providers are interested in herbal medicines. Therefore we aim to study the effectiveness of phytoestrogens on the severity of cyclic mastalgia. Methods  To carry out the present study, English electronic resources such as the Cochrane Library, ISI Web of Science, Scopus, and PubMed were used systematically and with no time limitation up to February 10, 2020. Results  In total, 20 studies were included in the present meta-analysis. The results of the meta-analysis showed that herbal medicines versus the control group (standard mean difference [SMD] = - 0.585; 95% confidence interval [CI]: - 0.728–- 0.44; heterogeneity; p  = 0.02; I2 = 42%), herbal medicines versus the B group (SMD = - 0.59; 95%CI: - 0.75–- 0.44; heterogeneity; p  = 0.03; I2 = 42%), and its subgroups, such as phytoestrogen (SMD = - 0.691; 95%CI: - 0.82–- 0.55; heterogeneity; p  = 0.669; I2 = 0%), Vitex-agnus-castus (SMD = - 0.642; 95%CI: - 0.84–- 0.44; p  < 0.001; p  = 203; I2 = 32%), flaxseed (SMD = - 0.63; 95%CI: - 0.901–- 0.367; p  = 0.871; I2 = 0%), and evening primrose (SMD= - 0.485; 95%CI:- 0.84–- 0.12; p  = 0.008; heterogeneity; p  = 0.06; I2 = 56%] may have effective and helpful effects on improving cyclic breast mastalgia. Also, chamomile, isoflavone, cinnamon, and nigella sativa significantly reduced mastalgia symptoms. Conclusion  Herbal medicines and their subgroups may have effective and helpful effects on improving cyclic breast mastalgia. The findings of our meta-analysis must be done cautiously because low methodological quality in some evaluated studies of this systematic review.


Introduction
Breast pain may be divided in two major categories: cyclic pain and noncyclic pain. 1,2 Cyclic breast pain exacerbates with the onset of the second half of the menstrual period and alleviates with the onset of menstrual bleeding; it is also distributed bilaterally toward the upper arms and armpits. 3 It may last > 5 days and $ 30% of women with mastalgia 4 and 11% of women may suffer from pain for 7 days. There are different studies on the prevalence of cyclic breast pain, which has been reported to range from 30 to 70%. 3 Breast pain may provoke anxiety and concern regarding breast cancer among patients; in turn, this concern may impose a high financial burden on the healthcare system due to unnecessary medical referrals and the performance of various diagnostic procedures, such as mammography and biopsy. 5 It also interferes with daily activities, sexual, physical, and social activities. 6 The etiology of breast pain is still unknown. However, the most accepted etiology is related to disturbance in concentration of estrogen, progesterone, and prolactin and the responsiveness of target organs to these hormones Nutritional and psychological causes, water retention in the body, and body and breast weight gain are considered other causes of cyclic mastalgia. 7 Different methods have been used for decreasing mastalgia. Pharmaceutical treatments include danazol, bromocriptine, and tamoxifen, and nonpharmaceutical treatments include supplements, oils, and herbal medicines. 6 Different studies proved that vitamin E is not effective for mastalgia. Although using drugs is associated with excessive expenses, there are also common side effects that renders them inneficient. 8 Meanwhile, tamoxifen has better therapeutic effects and fewer side effects than danazol, so it is mostly used. 9 The use of medicinal plants and herbal medicines has increased recently. Many studies were carried out on the use of herbal medicines for complications of menopause, dysmenorrhea, premenstrual syndrome, mastalgia, etc. 10 Most women, researchers, and healthcare providers have been interested in herbal medicines and phytoestrogens. Phytoestrogens are some compounds that are similar to 17-β-Sterol in terms of structure and function, or may have some effects similar to estrogens. 11 Phytoestrogens include several groups of compounds such as lignans, isoflavones, and coumestans. 12 There is much research on the effects of phytoestrogens on the severity of cyclic mastalgia. [13][14][15][16] Currently, danazol is used as the only effective treatment licensed for mastalgia associated with side effects. Tamoxifen as a third-line therapy is not currently licensed for breast pain treatment. 17 We have identified new studies that met the inclusion criteria that were not included in the previous systematic reviews. The purpose of the present study was to investigate the effectiveness of phytoestrogens on the severity of cyclic mastalgia.

Methods
English electronic resources such as ISI Web of Science, Scopus, PubMed, and Cochrane Library were used systematically and with no limitations up to February 10, 2020, in order to carry out the present study. The following keywords were used to find out research articles related to the effects of herbal medicines on cyclic mastalgia: (Mastalgia) and (Complementary treatments OR alternative treatments OR phytomedicine OR herbal treatments OR alternative medicine OR complementary medicine OR Vitex agnus-castus OR chaste OR flaxseed OR isoflavones OR soy OR Matricaria chamomilla OR chamomile OR Nigella Sativa OR Cinnamon. The references of the included articles and review articles on the subject of the present study were also carefully reviewed to complete the search. The search results from these five databases were merged and duplicates were deleted (based on the same title, year of publication, and name of the author).
Two authors independently investigated the title and abstract of articles, and the complete articles were extracted and investigated when they found that the subject is related to the purpose of the current research.
All clinical trials investigated the effect of oral or topical herbal therapies in the treatment of cyclic or noncyclic mastalgia. The intervention included women receiving herbal medicines as monotherapy or in combination with other chemical or herbal medications. Placebo, herbal medicine, chemical medication, usual care, and no interven tion considered as control group.
We also excluded conference papers, review papers, Editor's Notes, letters, case reports, and animal studies. In cases in which several reports from a study appeared to have been published, only one with more complete information was included, and the others were deleted. These cases were identified by controlling the similarity of the team of authors, the center and the period of the study, and the reported statistical results.
The selection of related articles was carried out by two independent reviewers within two steps. In the screening phase, the titles were read first, and a decision was made to enter the analysis. In case of any ambiguity in the inclusion of the article, the abstracts were reviewed to match their title and abstract with the inclusion and exclusion criteria. Cases that were suspicious and required to be fully read entered the second stage. In the second phase, the full text of the reviewed articles and the articles that fully complied with the inclusion and exclusion criteria were entered into a systematic review. All included articles, review articles, and references of articles on the study subject were also carefully reviewed to complete the search.
The data extraction table was designed by the research team and each article in the present study was reviewed by two independent researchers. The following data were extracted and reported in the table: Authors, country, age of the patients, duration of treatment, number of subjects submitted to the intervention, type of control of the intervention, and assessment tool results (Chart 1).

Evaluating the Quality of Articles
The Final Jadad scale including three items was used to evaluate the quality of articles. 31 These items was considered in terms of randomization (whether randomization was done and whether it was done appropriately), blinding (whether the trial was blinded and whether it was done appropriately), reporting account of all patients (Chart 2).

Statistical Analysis
The software Comprehensive Meta-analysis (CMA) version 2 (Biostat Inc. Englewood, NJ, USA) was used to perform the data analysis. The heterogeneity index of studies was determined by the I2 test and the Q Cochran test. According to the results of Higgins et al. 32 , it is considered that values < 25% show low heterogeneity; values between 25 and 75% show moderate heterogeneity; and values > 75% shows high levels of heterogeneity. According to the results of heterogeneity, random was used to report the effect of phytoestrogens if heterogeneity was 25 percent or higher instead of fixed effect. Forest plot was used to demonstrate the results of the meta-analysis in which the size of the squares shows the number of samples of each, and lines drawn on both sides show the 95% confidence interval (CI) for the effects of each study.

Flaxseed versus Placebo
The results of analyzing flaxseed with two studies 10,16 showed that women in the flaxseed group reported significantly less pain than those in the control group (SMD ¼ -0.63; 95%CI: -0.901--0.367; p ¼ 0.871; I2 ¼ 0%) (►Fig. 6). Fig. 3 Effects of herbal medicines versus placebo on cyclical mastalgia. The horizontal lines denote the 95% confidence interval; ■ point estimate (size of the square corresponds to its weight); ♦, combined overall effect of treatment. Fig. 4 Effects of phytoestrogens on mastalgia. The horizontal lines denote the 95% confidence interval; ■ point estimate (size of the square corresponds to its weight); ♦, combined overall effect of treatment.

Hypericum Perforatum L. versus Placebo
The analysis results showed that the effects of Hypericum perforatum L. and placebo were the same in relieving breast pain (SMD ¼ -0.16; 95%CI: -0.41--0.08; p ¼ 0.2; heterogeneity; p ¼ 0.55; I2 ¼ 0%; fixed effect model; 2 trials) (►Fig. 7). 28,30 Evening Primrose versus Placebo The analysis results showed that women in the evening primrose group reported significantly less pain than those in the control group (SMD ¼ -0.485; 95%CI: -0.84--0.12 ; p ¼ 0.008; heterogeneity; p ¼ 0.06; I2 ¼ 56%; random effect model) (►Fig. 8). 9,19,21,25,28 Sensitivity analysis was conducted due to moderate heterogeneity between studies, and the effect of each study on the final result was evaluated separately. None of the studies had a significant effect on the final result and heterogeneity of the present study.
Chamomile A significant reduction in pain was observed in both groups (chamomile and placebo) after 2 months (p < 0.0001 and p ¼ 0.048, respectively) compared with baseline and between the two groups (p ¼ 0.007). 15

Isoflavone
The reduction in pain was 13% for placebo, 44% for 40 mg of isoflavone per day, and 31% for 80 mg per day. There was a significant difference between groups. 24 Fig. 5 Effects of Vitex-agnus-castus on mastalgia. The horizontal lines denote the 95% confidence interval; ■ point estimate (size of the square corresponds to its weight); ♦, combined overall effect of treatment. Fig. 6 Effects of flaxseed on mastalgia. The horizontal lines denote the 95% confidence interval; ■ point estimate (size of the square corresponds to its weight); ♦, combined overall effect of treatment.

Cinnamon
There was a statistically significant difference between the two groups in the mean pain scores at the end of the 1 st and 2 nd months (p < 0.001 and p ¼ 0.02), meaning that the intensity of the pain at the end of the 1 st and 2 nd months were significantly lower in the intervention group than in the control group. 13

Nigella Sativa
A significant reduction in pain was seen in the Nigella Sativa group compared with the placebo group based on the visual analogue scale (VAS) (p ¼ 0.002). 10

Evening primrose versus Vitagnus
The mean pain decreased significantly in both the evening primrose (p ¼ 0.004) and in the vitagnus (p < 0.001) groups. Vitagnus was more effective than primrose. The authors did not report a p-value. 33

Vitamin E versus Flaxseed Oil
Breast pain decreased significantly in both the vitamin E and flaxseed oil groups during the 1 st and 2 nd months (p-value among groups < 0.001). However, the mean breast pain was not significantly different between the two groups, which were not different from each other at the end of the 1 st (p ¼ 0.54) and 2 nd months (p ¼ 0.73). 34

Danazol versus Evening Primrose
The overall response with danazol was 76%, in contrast with a 68% response in patients treated with evening primrose. 35 A clinically useful response was observed in 76% cyclical mastalgia and in 36% of those with noncyclical mastalgia treated with danazol, and in 55% of the patients with cyclical mastalgia and in 33% for those with noncyclical mastalgia treated with evening primrose oil. 20

Evening Primrose versus Bromocriptine
A clinically useful response was observed in 50% of the patients with cyclical mastalgia and in 24% of those with noncyclical mastalgia treated with bromocriptine, and in 55% of the patients with cyclical mastalgia and in 33% of those with noncyclical mastalgia treated with evening primrose oil. 20 Fig. 7 Effects of Hypericum perforatum L. on mastalgia. The horizontal lines denote the 95% confidence interval; ■ point estimate (size of the square corresponds to its weight); ♦, combined overall effect of treatment. Fig. 8 Effects of evening primrose on mastalgia. The horizontal lines denote the 95% confidence interval; ■ point estimate (size of the square corresponds to its weight); ♦, combined overall effect of treatment.

Vitex Agnus Castus with Meloxicam
No significant difference was observed between Vitexagnus-castus and meloxicam. 22 • The present study showed that GLA (Efamast) efficacy did not differ from that of placebo fatty acids, regardless of whether or not antioxidant vitamins were present.

Flaxseed and Vitex-agnus-castus
Patients with mastalgia in both the flaxseed and the Vitexagnus-castus groups reported a significant decrease in breast pain intensity and breast pain length in comparison with placebo (p < 0.01). However, no significant difference was observed between flaxseed and Vitex-agnus-castus in the 1 st and 2 nd months. 2

Discussion
Mastalgia is one of the common problems experienced by women worldwide during reproductive period effects. Drugs like tamoxifen, danazol, and bromocriptine were associated with side effects. As a result, it caused both patients and health providers are interested in herbal medicines. 35,36 According to our investigation, the present research is considered the first meta-analysis on clinical trials that studied the effectiveness of herbal medicines and their subgroups on cyclic mastalgia. Three studies were carried out on vitagnus, 2,10,22,25 one study on nigella sativa, 14 one study on cinnamon, 13 one on isoflavones, 24 two studies on Hypericum perforatum L, 28,30 one study on chamomile, 15 five studies on evening primrose, 9,19,21,25,28 one study on isoflavone, 24 one study compared evening primrose with bromocriptine, 20 vitex agnus castus with meloxicam, 22 and flaxseed with Vitex-agnus-castus. 2 The results of the present research demonstrate that phytoestrogen leads to improvement of cyclic mastalgia compared with placebo. 2,10,[13][14][15]18,22,[24][25][26] Similarly, nigella sativa, chamomile, cinnamon, and red clover may have helpful effects in improving cyclic mastalgia. According to the result of a study, it can be said that chamomile can significantly reduce the severity of cyclic mastalgia compared with placebo. 15 In vitro, chamomile can inhibit both the function of cyclooxygenase and lipoxygenase; consequently, the production of prostaglandins and leukotrienes is inhibited. 37 This plant is also used as antioxidant, analgesic, antiviral, antiinflammatory, and antiseptic. 38 According to Gharaiy et al. study, cinnamon is more effective than placebo to reduce the severity of breast pain. 13 Cinnamon contains eugenol, a compound that can prevent prostaglandin biosynthesis and also has anti-inflammatory effects. Research on cinnamon pharmacology and toxicology demonstrate no risk in consuming it. 39 Nigella sativa can relieve breast pain from cyclical mastalgia. 14 This finding is consistent with animal models, as the aqueous extract of N. sativa had anti-inflammatory and analgesic antipyretic effects in albino Wistar rats and albino Swiss mice. 40 Thymoquinone is one of the major compounds of N. sativa, 41 with analgesic, 42 anti-inflammatory, 43 antioxidative, 44 and antioxidative stress effects (Bhandari, 2014).
Nigella sativa inhibits inflammatory mediators such as prostaglandins and leukotrienes, macrophage function, NK antitumor activity, amends splenocyte proliferation and Th1/Th2 cytokine profile. 45 The physiological effect of nigella sativa is related to its volatile oil, and thymoquinone is considered one of its active elements with anti-inflammatory effect. 46 The process of inflammation would be regulated by lipoxygenase and cyclooxygenase. Inhibiting lipoxygenase and cyclooxygenase processes prevents the metabolism of arachidonic acid and controls the production of prostaglandins and leukotrienes. 47 Our meta-analysis with studies study shows that flaxseed can reduce the severity of cyclic mastalgia. 2,16 Flaxseed inhibited prostaglandin (PGE2), leukotriene-, histamine-, and bradykinin-induced inflammation, and arachidonic acid-induced inflammation. Flaxseed oil also inhibited both the cyclooxygenase and lipoxygenase pathways of the arachidonate metabolism. 48 Vitex-agnus-castus is known as chaste tree. 49 It is a tree with fingered leaves and cylindrical flowers that grows in the Mediterranean region and Eastern Asia; it has brown fruits which smell of pepper. Its extract is used to treat postpartum hemorrhage. 50 This plant contains progestins, essential oils, diterpenoids, iridoids, flavonoids and ketosteroids. 51 Vitex agnus castus contains iridoids, flavonoids, diterpenoids, and progestins, as well as essential and fatty oils in the fruits, flowers, and leaves. 52 The antiprolactin effect of this plant was evident in previous studies and it is more effective in the treatment premenstrual syndrome. 53 The results of the present meta-analysis showed that, compared with placebo, Vitex-agnus-castus can significantly reduce the severity of cyclic mastalgia. 2,10,18,22,25 The exact mechanism of its effects has not been proved yet but it seems that its effect on the hypothalamus-pituitary axis reduces FSH and prolactin levels and also increases the level of LH. 54 The effect of Vitex Agnus-castus extract on the treatment of luteal phase defects due to latent hyperprolactinemia is investigated. The findings of the study showed a decrease in prolactin levels, normalization of shortened luteal phases duration, and elimination of luteal progesterone. 55 Estimated high to moderate heterogeneity was observed between studies in the evening primrose and Vitex-agnus-castus subgroups, which may be related to different amounts of effective ingredients, different ages of the participants, and different mastalgia severity and pattern of (cyclical and noncyclical). Cyclic mastalgia is more frequent in the 2 nd and 3 rd decades of life. 56 Thus, age may have an effect on mastalgia; therefore, to clarify the relationship between age and mastalgia severity, confounders such as age need to be adjusted in future studies. 56 The limited number of studies is a reason for the second limitation of the present study, because it was not possible to evaluate the heterogeneity of studies by metaregression. The third limitation is the level of methodological quality in some evaluated studies of this systematic review was evident. The problems we have observed in these studies were inappropriate methods of randomization and doubleblinding and lack of reportingintention-to-treat analysis. It is suggested that future studies future studies should adhere to CONSORT guidelines. The limited number of studies and their small sample sizes are the fourth imitation of the present study, and more studies with larger sample sizes are warranted. The fifth limitation is that some of the studies have a small sample size, and any enhancement in sample size may have changed the results of these studies. Some studies had no placebo group, so they were not included in the present study. Some studies were designed with test and post-test with no control group and were excluded from the present study, so we suggested designing future studies with placebo and control groups. The sixth limitation is that phytoestrogens are divided into four groups (isoflavones, gensitin, dydizin, and glycine). We suggest that future studies investigate the effect on cyclic mastalgia of other phytoestrogen compounds in the aforementioned groups so that their results can help us to reach a better understanding of their function. The seventh limitation is that generalizing the research findings must be done cautiously because all of the studies were conducted in Iran. The length of treatment was short in most studies and therapeutic effects have not been evaluated after discontinuing the drugs. Finally, all phytoestrogens evaluated in the present meta-analysis had positive effects on the severity of mastalgia, but the function of these phytoestrogens was not investigated in any of the included studies. We recommend the investigation of this important issue in future studies. Since phytoestrogens have a positive effect on cyclic mastalgia, we suggest investigating the effect of phytoestrogens on noncyclic mastalgia; further studies with longer duration and with a follow-up phase should be performed in order to investigate the maintenance of their effectiveness. Some studies have reported that such an assurance the women obtain when clinical breast examination can effect on the intensity of cyclical mastalgia 16 the confounding variables should be controlled in future study.

Conclusion
Due to the important effect of the health of women in their function in the family and in society and to the fact that mastalgia may cause disruption on their activities and also the positive effect of the effectiveness of herbal medicines, this study was peformed to investigate the effectiveness of herbal medicines on the severity of cyclic mastalgia. The findings of this study showed that herbal medicines such as nigella sativa, chamomile, flaxseed, vitex-agnus-castus and red clover can be considered as an effective and helpful method in improving cyclic mastalgia. The findings of the included studies must be interpreted cautiously due to the high level of heterogeneity between studies, the limited number of studies, and their small sample sizes.