Menopause is a natural growth transition stage in every woman [1]. During menopause, the activities of estrogen and progesterone secreted by the ovaries dramatically decrease [2,3]. Women experience physical, mental, social, and psychological changes during menopause, which results in cardiovascular diseases, osteoporosis, bone fracture, and even Alzheimer disease in the long term [4-6]. Menopause with complications such as severe hot flash, sudden sweats, fatigue, and dizziness, as well as physiological complications, leads to osteoporosis, ovarian atrophy, decrease in sexual hormone levels, increase in weight, and depression. Thus, acquiring good knowledge about effective treatments to reduce mental and psychological problems of menopausal women is of high value and importance [7-10].

Use of various alternative or complementary treatments to reduce the undesirable symptoms of menopause is widely accepted nowadays. Among such treatments, phytoestrogens are used as hormonal therapies in menopausal women; these can have less side effects because of their herbal origin [11]. Phytoestrogens are found in soybean, beans, cereals, and vegetables and have an estradiol-like function [12].

Administration of herbal medicines has been popular since a long time for the cure of irregular menstruation, menopausal complications, and menstrual pain. In Iranian traditional medicine, several herbal medicines have been suggested to be effective in alleviating menopausal symptoms. Vitex agnus-castus extracts (panj-angosht in Persian) is a native plant of the Mediterranean countries has a long history in traditional medicine. Botanical studies, cultivation, and pharmacognosy of Vitex started in Iran in 1991, and medicinal products were introduced in 1996 [13]. Rates of complication, including mild upset stomach, rash, and itching, are low; complications are seen in approximately 2% of users [14-17]. Vitex has numerous uses in traditional medicine, and primary studies have demonstrated its effectiveness in decreasing menopausal complications [18-20]. The fruit of this plant is administered as treatment for menopausal complaints. Currently, in European and American countries, the use of the Vitex fruit for its therapeutic effects on women with reproductive problems, premenstrual syndrome, infertility, and hyperprolactinemia is common. Despite the lack of clinical trials designed to study the effects of this plant on menopause-related symptoms, pharmacological evidence denoting its dopaminergic activity, closeness to opioid receptors, and ability to increase melatonin secretion support the effectiveness of Vitex for reducing menopausal symptoms [16].

Nearly one-third of a woman’s lifetime is in the postmenopausal years. Menopause causes various complications; hence, searching for a treatment with less side effects and reasonable effectiveness for menopausal problems seems important and necessary. Herbal medicines have less side effects than chemical medications.

Clinical trials conducted on the efficacy of Vitex in improving menopausal symptoms only examined the general score for menopause based on the Greene Questionnaire. In addition to the total score, relevant symptoms, including anxiety, depression, somatic complications, and vasomotor and sexual dysfunctions, were investigated.

This study was a randomized double-blind clinical trial with a pretestposttest design registered in the Iranian clinical trial website coded as IRCT 2016120528967N3.

In this randomized double-blind clinical trial, 159 eligible subjects were evaluated, of whom 98 were excluded (68 based on the inclusion and exclusion criteria, and 30 owing to reluctance). Sixty-one subjects were randomly assigned to the two groups, the Vitex group (n=31) and placebo group (n=30), and were followed up for 8 weeks.

During the study, five subjects in the Vitex group (due to side effects) and four in the treatment group (due to side effects and unwillingness to continue to use) dropped out. A total of 26 subjects each were randomly allocated to the Vitex and placebo groups and analyzed (CONSORT flow diagram) (Figure 1).

The age range of the participants was 48–58 years. The mean ages in the Vitex (52.85 years) and placebo groups (52.16 years) were not statistically significant (P=0.38). In the Vitex group, 23 (88.05) were unemployed and 3 (11.5) were employed. In the placebo group, 24 (92.04) were housewives and 2 (7.06) were employed. No statistically significant relationship was found between employment status and the study groups (P=0.32). In terms of marital status, in the Vitex group, 2 subjects (7.7) were single and 24 (92.03) were married. In addition, in the placebo group, 2 (7.7) were single and 24 (92.03) were married. No significant difference in the distribution of marital status was observed between the two groups (P=0.52). In addition, no significant relationship was found between income level and mean body mass index in the study groups (P=0.16, P=0.52, respectively). A number of years divorced of 10–18 years was reported in the two groups, with a mean of 13.76 in the Vitex group and 13.50 in the placebo group. No significant difference was found between the two groups (P=0.58). The pregnancy rate was also reported, with a mean of 3.77 in the Vitex group and 3.74 in the placebo group (P=0.95). The mean difference was not significant between the two groups (P=0.95). The menopausal age was reported in the two groups to be between the ages of 46 to 57 years, the mean of which was not significantly different between the Vitex group (50.94) and placebo group (50.84; P=0.89). The years elapsed since menopause, with a variation range of 1–3 years, was also higher in the Vitex group than in the placebo group (1.32), with a statistically significant difference (P<0.05). The number of hot flashes per day with a variation range of 3 to 20 times was reported in the Vitex and placebo groups, with means of 8.58 and 9.24, respectively, which were not statistically significantly different between the two groups (P=0.74). As a result of Vitex and placebo use, 3 subjects (11.53) in the Vitex group experienced nausea and 2 (7.69) experienced itching. In the placebo group, only 1 subject (3.84) had nausea, with no significant difference in the incidence of side effects between the two groups (P=0.07) (Table 1).

The results of the comparison of the mean scores related to the menopausal symptoms at the beginning of the study between the Vitex and placebo groups by the independent-samples T-test (differences with significance level of <5% were significant) (Table 2), including anxiety, depression, somatic complications, vasomotor dysfunction, sexual dysfunction, and total dysfunction, showed that in the Vitex group, the mean scores were higher. However, this comparison between complications was not statistically meaningful at this point (i.e., before the intervention; P>0.05).

After 8 weeks of follow-up and at the end of study, the results of the comparison between the Vitex and placebo groups regarding the mean scores of menopausal complications showed that the means were lower in the Vitex group for all complications.

The comparison of these results showed that at a margin of error of 5%, the mean scores for anxiety and for vasomotor and total dysfunctions were significantly different between the Vitex and placebo groups (P<0.0001), leaving decreases in the mean sores for anxiety and vasomotor and total dysfunction to 3.2 and 3 times lower in the treatment group, respectively. On the other hand, at the end of study, the mean scores for depression, somatic complications, and sexual dysfunction variables had no significant statistical differences between the Vitex and placebo groups (Table 2).

This research was conducted to determine the effect of the Vitex plant extract on menopausal symptoms in comparison with that of placebo. Results showed that in the Vitex group, the total scores for menopause, anxiety, and vasomotor dysfunction were meaningfully diminished after the intervention. The notable point was that along with the Vitex group, the placebo group showed decreased mean scores for menopausal symptoms, which could be attributed to the suggestibility effect in this group, although the recovery process of the menopausal symptoms in the Vitex group was significantly more prominent that that in the placebo group.

The results of this study are congruent with those of the study by van Die et al. [16] in 2009 that reported the effectiveness of Vitex agnus-castus extracts in the treatment of menopause-related complaints. They are also in agreement with the results of the study by Abbaspoor et al. [20] who conducted a double-blind clinical trial in 2011 to assess the effects of Vitex on primary menopausal symptoms and revealed that Vitex was effective in reducing primary vasomotor symptoms in women. Berger et al. [23] in 2000 also showed that Vitex was effective for menopausal symptoms. In explaining this finding, the mechanism of the main effect of the plants in the treatment of some female diseases seems to be their effects on body hormones. Studies have demonstrated that some important plant components, including flavonoids, directly affect the pituitary gland, especially the part of the gland that secretes luteinizing hormone, which increases the progesterone level and modify disorders caused by decreases in hormone levels. Previous studies reported that Vitex can decrease prolactin levels in rats. This study also mentioned that Vitex can inhibit prolactin release by binding to dopamine receptors [24,25].

Vitex contains phytoestrogens, which are weak estrogen agonists; therefore, it can be conceptualized that in low-estrogen environments, similar to that in as in menopausal women, this plant can exert more radical estrogenic effects [26].

Vasomotor dysfunction is the most problematic symptom in menopause. The prevalence of vasomotor dysfunction in European, Malaysian, Chinese, and Singaporean menopausal women is estimated to be 70%–80%, 18%, and 14%, respectively, which is attributed to the differences in dietary phytoestrogen levels in these areas [27]. In a randomized controlled assessment by Knight and Eden [28] in 1995, decreasing trends in the prevalence rates of headache, sleep problems, depression, and irritability were observed among users of phytoestrogencontaining diets, denoting the fact that phytoestrogens can play a role in reducing menopausal symptoms, similar to Vitex. No significant differences in the mean scores of sexual dysfunction, physical complications, and depression were found between the Vitex and placebo groups. In the explanation of this finding, it can be told that sexual contact in menopause, in addition to physiological factors, are affected by individual, social, and psychological factors. Some women in their menopausal phase are less concerned about their sexual relationships and have less sexual activity [29], which can affect the outcome of the treatment.

In addition, in the explanation for the same score for physical complications and depression in the Vitex and placebo groups, some stressors such as family problems, negative attitudes to physical changes, and factors associated with menopause may be confounding. We can conclude that in the treatment of menopausal symptoms, psychological and social factors should be considered in therapeutic approaches. Unfortunately, in the present study, it was emphasized only in the biological dimensions.

Although this study showed that Vitex can be effective in alleviating menopausal symptoms, further research is essential to clarify the degree of effectiveness and the mechanisms of action of Vitex.

Some limitations of this study were the small number of subjects, the absence of follow-up findings, and use of a questionnaire to record menopausal symptoms that can potentially give rise to respondent bias. It is advisable to use larger sample sizes and follow the results of interventions.

In conclusion, Vitex plant extract can be considered as an inexpensive, effective, and safe treatment with no side effects that can be applied as a non-hormonal remedy option along with other therapy methods available for menopausal complications.