Abstract
Objective : To evaluate the effects of a herbo-mineral phytoestrogen formulation (Drug A) containing soy isoflavones in Indian women presenting with signs and symptoms of menopause.

Material and Methods : We conducted a prospective, randomized, double blind, placebo controlled trial in a public hospital in India. Sixty peri- and post-menopausal women with symptoms related to menopause were randomized and assigned to either group A (active drug) or group B (placebo). Menopausal symptoms were graded along a scale (based on Kupperman Index) at baseline and changes were noted every two months, and thereafter for a total of 6 months.

Results : Data from a total of 58 patients were found eligible for analysis (28 in active group, 30 in placebo). The group that received the active drug showed 30-40% improvement in psychological symptoms as compared to placebo (p < 0.05, chi-square test). This group also reported an overall sense of well-being as compared to the placebo group. Improvement was noted in vasomotor symptoms, symptoms relating to sexual activity and urinary symptoms in the group receiving Drug A.

Conclusion : The herbo-mineral phytoestrogen formulation (Drug A) containing soy isoflavones is effective in the management of the symptoms in menopausal women as compared to placebo.

Introduction
Menopause is associated with a variety of symptoms, including hot flushes, night sweats, palpitations, insomnia, depression, memory or concentration difficulties, and vaginal dryness. In some women, these symptoms could be severe and could adversely affect the quality of life. In such women, it becomes imperative to treat menopausal symptoms effectively so as to provide relief from the disturbing symptoms. However, management of menopausal symptoms poses a significant challenge to clinicians. On one hand, it is important to provide quick relief from the distressing symptoms of menopause, while on the other, the long-term safety of the treatment remains an important concern. Over the past few years, phytoestrogens have emerged as an important option in the management of menopausal symptoms. Phytoestrogens have been proposed to be safer than the conventional HRT, while at the same time, they could also be utilized in alleviating the symptoms.

In recent years, a wealth of epidemiological data has emerged, which has pointed towards the beneficial effects of soy isoflavones on menopausal symptoms. In particular, studies conducted in Japan have shown that Japanese women, who have a higher content of soy products in their diet, experience lower incidence of hot flushes. In addition, it has also been reported that higher intake of soy products reduces the severity of various vasomotor and psychosomatic symptoms associated with menopause.1,2

Higher consumption of soy isoflavones has been shown to exert additional beneficial effects on bone metabolism and thereby prevent osteoporosis.3 It has also been observed that several Asian populations that have low rates of breast cancer consume higher quantities of phytoestrogens (20–80 mg/day), almost entirely derived from soy.4 The ingestion of soy protein has also been associated with a decrease in total cholesterol, LDL and triglycerides and an increase in HDL cholesterol.5 Phytoestrogen intake has been demonstrated to decrease bone turnover and favourably alter blood lipids in postmenopausal women who already have high daily dietary intakes of soybean products.6

In view of the epidemiological and clinical evidence available in favour of phytoestrogens, the present study was aimed at studying the effects of a herbo-mineral phytoestrogen formulation (Drug A) in Indian women presenting with signs and symptoms of menopause.

Material and Methods
This was a prospective, randomized, double blind, placebo controlled trial conducted in a tertiary care hospital in Mumbai, India. A written approval was obtained from the Institutional Ethics Committee prior to the initiation of the study and an informed consent was obtained from all participants in the trial.

A total of 60 peri- and post-menopausal women who presented to the gynaecology out patient department with symptoms of menopause were recruited to the study. The exclusion criteria were (i) women who did not have any symptoms (ii) women who had past or present history of HRT use (iii) women who had a significant medical illness such as hypertension or diabetes mellitus that was uncontrolled (iv) women with abnormal vaginal bleeding wherein dysfunctional uterine bleeding was not confirmed.

After obtaining informed consent, a detailed medical and gynaecological/obstetric history was obtained, and a thorough clinical examination, both systemic and local, was done. A detailed history of all symptoms was taken by the same clinician at the first examination and then subsequently throughout the study.
All patients underwent investigations including haematology, biochemistry, urinalysis, screening sonography, pap smear examination and mammography. It was ensured that all investigations were within normal limits before randomizing the patients.

The patients were randomized according to a random number chart and assigned to either group A (active drug, each capsule containing soy isoflavones, lignans, antioxidants and plant-based ingredients) or group B (placebo). They were administered one capsule twice daily for a period of six months.
For quantitative recording and analysis, symptoms, based on Kupperman Index, were graded along the following scale: absent, mild, moderate, and severe (Table 1).

The symptoms were grouped together based on their clinical relationship with each other, for example:

• Vasomotor symptoms such as hot flushes and night sweats
• Symptoms related to sexual activity such as change in sexual desire, painful intercourse and vaginal dryness during intercourse
• Urinary symptoms such as frequency of urination, urgency and incontinence
• Psychological symptoms such as anxiety, irritability, depression, tiredness, insomnia, lethargy, decrease in concentration and impaired memory
• Musculoskeletal symptoms such as joint pains, low backache, diffuse aches and skin changes
• Miscellaneous complaints such as weight gain, feeling of fullness and heaviness.

Table 2 : Baseline characteristics of the treatment groups Symptom / characteristic Active Drug Placebo group Mean age (yrs) 49.4 48.6 Mean body weight (kg) 58.5 59.7 Vasomotor Symptoms Hot flushes (%) 86.2 82.8 Night sweats (%) 77.9 75.4 Symptoms Related to Sexual Activity Change in sexual desire (%) 62.9 60.4 Dry vagina and painful intercourse (%) 75.9 71.8 Urinary Symptoms Urinary urgency / incontinence (%) 60.0 59.3 Psychological Symptoms Anxiety (%) 78.8 77.6 Irritability (%) 69.2 68.7 Depression (%) 53.3 56.4 Insomnia (%) 62.4 66.3 Tiredness (%) 85.8 88.6 Inability to concentrate (%) 49.6 48.3 Impaired memory (%) 57.4 55.7 Musculoskeletal Symptoms Low back pain (%) 88.4 87.6 Joint pains and generalized aches (%) 90.5 91.1 Miscellaneous Symptoms Weight gain (%) 79.4 78.5 Feeling bloated (%) 58.3 57.2

Table 3 : Effect of Drug A vs placebo on psychological symptoms Symptom Drug A group Placebo group P value No change Improvement No change Improvement Anxiety p 28.6 43.0 66.7 0.0 < 0.05 Irritability 21.4 50.0 53.3 0.0 p < 0.05 Depression 28.6 43.0 53.3 0.0 p < 0.05 Insomnia 35.7 28.6 53.3 0.0 p < 0.05 Feeling tired 50.0 28.6 46.7 0.0 p < 0.05 Lethargy 42.9 35.6 46.7 0.0 p < 0.05 Decrease in concentration 28.6 35.7 46.7 0.0 p < 0.05   Fig. 1 : Effect of Drug A vs Placebo on Psychological Symptoms. The numbers on the vertical axis indicate the percentage of patients responding to Drug A and Placebo.

Symptom scores were recorded at the beginning of treatment and every two months thereafter. In order to minimize the observational differences, the symptom scores at various time intervals were recorded by the same clinician. The symptoms were tracked during the treatment period of 6 months. The values were subjected to chi-square test and a P value of < 0.05 was considered to indicate statistical significance.

Results
A total of 58 patients were found to be eligible for statistical analysis at the end of the study, out of whom 28 were from the active group and 30 from the placebo group. Two patients dropped out of the study because of reasons unrelated to the study medication. Table 2 provides the baseline characteristics of the patients in both the treatment groups at the time of recruitment to the study. Both the groups were comparable in terms of age, body weight and severity of symptoms.
Drug A treatment showed a significant improvement in psychological symptoms as compared to the placebo group. Table 3 and Fig. 1 summarize the findings of the active drug and placebo groups on psychological symptoms. The difference between the two groups was statistically significant (p < 0.05).

Patients in group A did not show deterioration in urinary symptoms, unlike patients in the placebo group, who showed deterioration in 40%. Further, in Group A, which received active drug, 35.7% of the patients reported an improvement in hot flushes, while the improvement in the placebo group was only 26.7%.
Similarly, in symptoms relating to sexual activity, active drug therapy led to an average improvement in up to 21.4% of patients, whereas placebo treatment led to deterioration in up to 40%. No significant improvement was observed in musculoskeletal and miscellaneous symptoms following therapy. Active drug was well tolerated with no side effects being reported relating to the therapy, except a mild feeling of bloating.

Discussion
Several studies have indicated that increased dietary intake of phytoestrogens reduces the impact of menopause. Groups consuming high phytoestrogen diets have been shown to have between 10 and 30 times higher urinary excretion of phytoestrogens compared to those consuming low phytoestrogen diet. In a study conducted by Dalais et al7, participants consuming high phytoestrogens reported reduction in hot flush rate, increase in vaginal cytology maturation index and increase in bone mineral content.

A study conducted by Nagata et al8 have shown that dietary phytoestrogen has a beneficial effect on psychological status. The investigators demonstrated that dietary soy produces a feeling of well-being in peri- and postmenopausal women. Colacurci et al9 have demonstrated that isoflavone treatment leads to a progressive and significant reduction in the number of hot flushes. Wilcox et al10 showed that dietary supplementation with isoflavones or lignans had an oestrogenic effect and led to improvement in maturation scores of vaginal epithelium on cytology.

The results obtained in the present study are in congruence with earlier findings. Similar to the findings of earlier studies, treatment with this phytoestrogen preparation showed improvement in psychological symptoms and hot flushes. Further, phytoestrogens have been reported to produce several other beneficial effects. A meta-analysis of 38 controlled clinical trials conducted by Anderson et al11 to examine the relation between soy protein consumption and serum lipid concentrations indicated that the ingestion of soy protein was associated with a decrease of 9.3% in total cholesterol, 12.9% in LDL, and 10.5% in triglycerides and an increase of 2.4% in HDL cholesterol.

The currently available data on phytoestrogens suggest that phytoestrogens are safe and can be used in management of menopausal symptoms. However, larger and in depth studies are required to ascertain whether they have a protective role in breast cancer and for any beneficial effects on the bone density and fracture risk.

Conclusion
The results of this double-blind, randomized, placebo-controlled study indicate that the herbo-mineral phytoestrogen formulation (Drug A) containing soy isoflavones is beneficial in management of symptoms of menopause such as psychological symptoms and hot flushes compared to placebo. Therefore, it is a promising option in the management of symptoms of menopause in the Indian population.

Acknowledgements
The authors thank all the patients who participated in this study. The authors also thank Charak Pharma Pvt. Ltd. for supporting the study and providing the phytoestrogen drug Evanova.

References

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