A novel mechanism: Erxian Decoction, a Chinese medicine formula, for relieving menopausal syndrome
Introduction
There were more than 477 million menopausal women in the world in 1998, and the number expected to reach 1.1 billion by 2025 (Uhl, 2008). Menopause is a process of normal aging, during which the level of estradiol secreted by the ovaries gradually declines, and menopausal women therefore have irregular menses and much higher incidences of physiological and mental changes, which severely disrupt their quality of life (Burger et al., 2007). The solution to overcome menopausal symptoms seems simple—hormone replacement therapy. Although the therapy has been widely practised for the past 50 years, it increases the risk of breast cancer and cardiovascular disease etc. (Ross et al., 2000, Vera and Rada, 2002). Therefore, it is desirable and urgent to explore the use of alternative medicine, especially Chinese medicine (Newton et al., 2002, Low Dog, 2005, Zhang et al., 2005).
Erxian Decoction (EXD), a popular Chinese medicine formula, consists of six Chinese medicinal herbs, Curculigo orchioides (Hypoxidaceae, rhizome), Epimedium brevicornum (Berberidaceae, whole herb), Morinda officinalis How (Rubiaceae, root), Angelica sinensis (Umbelliferae, root), Phellodendron chinense (Rutaceae, bark) and Anemarrhena asphodeloides (Anthericaceae, rhizome) (Ban, 2005). It has been clinically used in treatment of menopausal syndrome for more than 50 years. Nian et al. (2006) and Qin et al. (2008) report that EXD and its chemical constituents possess antiosteoporotic activity in ovariectomized rats and it can increase the estradiol level in serum. Many clinical reports demonstrated that EXD was effective in relieving menopausal syndrome via increasing the circulatory estradiol level (Li et al., 2007). Our recent systematic review also indicated that the efficacy of EXD was better than other forms of non-hormone replacement therapy, while there was no significant difference between the efficacy of EXD and hormone replacement therapy groups (Chen et al., 2008). However, the mechanism of action of EXD on stimulation of estradiol secretion for relieving menopause has not been reported so far.
Estradiol is bio-synthesized in ovarian granulosa cells. Ovarian aromatase Cyp19 is a critical enzyme for estradiol bio-synthesis (Simpson et al., 1994). In menopause, although the circulating level of FSH remains high for several years, it does not induce an increase of circulating estradiol level. Interestingly, previous studies showed that the estradiol level increased after administration of EXD (Fang et al., 1992, Nian et al., 2006, Chen et al., 2008). Along with aging and menopause, the activities of steriodogenic enzyme, aromatase, and antioxidant enzymes are also lowered (Okatani et al., 1993). We therefore hypothesize that EXD is effective in relieving menopausal syndrome through increasing the activation of aromatase and antioxidant enzymes. In this study, we propose to: (1) evaluate the steriodogenic activity of EXD by measuring the estradiol level in serum and mRNA level of aromatase in ovary and (2) evaluate the antioxidant activity of EXD by measuring the mRNA level of antioxidant enzymes, including superoxide dismutase-1 (SOD), catalase (CAT) and glutathione peroxidase (GPx-1), in liver.
Besides, the levels of main elements with reproductive toxicity, including arsenic (Chattopadhyay et al., 1999), cadmium (Nagata et al., 2005) and lead (WHO, 1995), were assessed using atomic absorption spectrophotometer (AAS) to ensure the safety of EXD extracts. A simple, rapid and valid chromatographic fingerprint with marker standards was developed using high-performance liquid chromatography with photodiode array detection (HPLC-DAD) for assessing quality consistency among the EXD extracts.
Section snippets
Herbal materials
The six plant materials, Curculigo orchioides, Epimedium brevicornum, Morinda officinalis How, Angelica sinensis, Phellodendron chinense and Anemarrhena asphodeloides (composition ratio: 12:12:10:10:9:9) (voucher numbers. CME140706-03, CME150906-11, CME050406-02, CME090706-12, CME100606-09 and CME180806-01) were collected from various sources and their identity was confirmed by Professor Zhengtao Wang, Department of Pharmacognosy, China Pharmaceutical University and voucher specimens were kept
The quality control
The contents of main toxic elements, including arsenic, cadmium and lead, were lower in EXD formulations compared with the standard in the Department of Health of the Government of Hong Kong Special Administrative Region. The results are summarized in Table 2.
For exploring most of detectable peaks in the HPLC chromatogram, the spectra of all eluted peaks found in the chromatogram of EXD were investigated with photodiode array detection. The chromatograms were generated under the detection
Discussion
In this study, an atomic absorption spectrophotometer and a reversed-phase HPLC with a photodiode array detection assay were used to evaluate the main toxic elements and the quality consistency among different batches of EXD extracts respectively. The contents of the main reproductive toxic elements in Chinese herbs, including arsenic, cadmium and lead, have been assessed in this study. Usually, higher contents of these toxic elements in Chinese herbs may be attributed to the uptake of these
Conclusion
In this study, we developed the comprehensive quality control methods to examine the main reproductive toxic elements, including arsenic, cadmium and lead, and to evaluate the quality consistency of EXD among different batches of EXD extract. These ensure the safety and quality of EXD extract. Furthermore, we explored the novel mechanism of EXD for relieving menopausal syndrome. EXD treatment up-regulated the mRNA levels of aromatase and CAT, and displayed estrogenic activity. These findings
Acknowledgements
This research was supported in part by a grant from Small Project Funding (no. 200607176131), Seed Funding Programme for Applied Research (no. 200802160025), the University of Hong Kong and Liu Hao Tsing Foundation Ltd. We also thank Ms. Cindy Lee for expert technical assistance.
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