| Background: Hyperplasia of Mammary Gland (HMG) refers to disordered mammary structure due to physiological hyperplasia or incomplete renewing of lobular mammary gland during the maturing period or with periodical change, pathologically presented by epithelial hyperplasia, fibrous hyperplasia or lymphocyte predominated inflammatory cell infiltration, generally entitled as mammary dysplasia. Among variety of mammary gland diseases, the incidence of HMG reaches 75%, it accounts for 40% diseases of women of childbearing age. The disease mainly affect women of age 20 through 50, which reaches a peak at age 45 to 50; and declines sharply after 50. Epidemiological data indicates that breast cancer is closely related to proliferative breast diseases, in particular mammary atypical hyperplasia. Domestic and overseas professionals consider that it's carcinomatous change rate accounts for 10～20%, the risk of the occurrence of breast cancer in women with HMG is 1.4 to 2.5 times higher than in healthy women. The transforming of normal mammary epithelial cells to malignant condition is a gradual process, around 15 to 35 years, owing to various internal and external factors. During this long transforming period of several decades, active interventions, such as improvement in the environment, behavior intervention, mental ease, medication treatment, etc. all can have positive regulatory effect on the immune function and endocrine function; it may reverse the disease process to reduce or to prevent the occurrence of breast cancer finally. Therefore, prevention and treatment of this disease has important clinical significance and broad application prospects. This disease belongs to the scope of Chinese Medicine "Ru Pi". Traditional Chinese Medicine (TCM) believes that kidney deficiency and liver Qi stagnation, disordered Qi and blood in Chong and Ren meridians are the root cause (Ben), Qi stagnation, accumulation of sputum, and blood stasis are symptoms and signs (Biao), diseased location is liver, spleen and kidney, it is characterized by Ben deficiency and Biao excess. Western medicine considers HMG is caused by endocrine disorders, estrogen level rising, disordered ratio of estrogen and progesterone, or an increase in estrogen receptor in mammary tissue. In terms of the treatment, western medicine often adopts the endocrine therapy or surgical therapy, however, there are some inadequacies, such as the efficacy can be good when taking medicine, while there is rebound phenomenon after drug withdrawal, short-term medication will interfere with hormone balance as well, the operation can be a stimulating factor to the mammary tissue around. Currently, TCM treatment, based on syndrome differentiation, has evident effect characterized by comprehensive advantages for proliferative benign mammary diseases, including syndrome differentiation treatment, formulated herbal medicine treatment and single herb treatment. Nevertheless, there are still some problems, there is no uniformed standard for syndrome type differentiation, some studies do not have control group, etc. In this paper, three different TCM treatments, i.e. Soothing Liver Qi, Regulating Chong and Ren Meridian, Tonifying Kidney and Soothing Liver Qi, are applied to treat rat with MGH, the effect was observed, the acting mechanism was explored. The study result has provided a new way of thinking for the treatment of this disease, which is effective, cost-effective, can be widely applied.Methods: Through intramuscular injection of estradiol benzoate and progesterone, rat model of MGH were produced. 60 rats were randomized into six groups with 10 in each group, all receive drug intervention. The analgesia experiment were conducted to compare the analgesic effect of different interventions; behavior indicators were observed, plasma sex hormone levels were detected including estradiol (E2), progesterone (P), pituitary prolactin (PRL), luteinizing hormone (LH), follicle-stimulating hormone (FSH); measure the height of the nipple on rats, to detect the degree of congestion and edema of mammary tissue; observe pathological signs through light microscope, focusing on the number of breast lobules of acinar, adenomatosis, acinar secretion phenomenon, and the ductal hyperplasia degree, to compare the effect of different interventions on mammary gland hyperplasia; detect ER, PR, P53 and the expression level of telomerase in rat's mammary tissue by immunohistochemistry method or by in situ hybridization method.Results: Treatment method of Soothing Liver Qi and Regulating Chong and Ren Meridian shows non-specific analgesic effect on mice model, better than either the treatment method of Soothing Liver Qi, or method of Regulating Chong and Ren Meridian, it is also better than Ru Pi Xiao group or tamoxifen group, all have statistical significance (P <0.05). This method can improve syndromes of kidney deficiency and liver Qi stagnation, i.e., pilo-erection, less fur-ray, lipsotrichi, lassitude, roach back, aversion to cold, unresponsive, irritable, fidget, with statistical significance (P < 0.05). Experiments also show that breast diameter significantly change in Tamoxifen group, or Ru Pi Xiao group, or Tonifying Kidney and Soothing Liver Qi group (referred as, mixed group, in following sections) (P <0.01), while there is no significant change for breast diameter in the group of Soothing Liver Qi, or Regulating Chong and Ren Meridian group (P> 0.05), this experiment indicates that the mixed group is superior to Soothing Liver Qi group or Regulating Chong and Ren Meridian group. With respect to decreasing nipple height, there is no apparent differences among the treatment groups, though there is significance when compared with blank control group (P <0.05). Morphological observation of mammary tissue of rats indicated that, group of applying treatment method of both Soothing Liver Qi and Regulating Chong and Ren Meridian has better effect against rat MGH induced by exogenous estrogen and progesterone. Regarding adjust the level of sex hormone, mixed group, tamoxifen group have a significant effect in reducing serum E2 level (P <0.01), meanwhile, Soothing Liver Qi group can effectively reduce the serum E2 level which is statistical significant (P <0.05); Soothing Liver Qi group, Regulating Chong and Ren Meridian group, mixed group significantly increase serum P level when compared with blank control group (P <0.05), further, there is a significant difference between the latter two groups (P <0.01); for the level of PRL and LH, there is no significant difference between treatment groups and control group (P> 0.05); besides, regulating Chong and Ren Meridian group can reduce FSH concentration compared with control group (P <0.05), the mixed group and the tamoxifen group can significantly reduce it's concentration (P <0.01). When mammary gland tissue manifested obvious hyperplasia morphologically, mammary ER, PR expression levels significantly increase. The mixed group shows effect of inhibiting mammary tissue hyperplasia, and decreasing ER, PR level, there is statistical significant when compared with blank model control group (P <0.01). Immunohistochemistry method was used to determine mutant P53 protein expression before and after the treatment, the result shows, P53 in mammary tissue of rat with HMG is much lower than that in normal rat and in mixed group, and the staining gray values between the latter two groups are similar, these signs indicate that P53 protein is increased in the mammary tissue of rat with HMG, herbs of Soothing Liver Qi and Tonifying Kidney can inhibit the production and release of P53 protein which has a protective effect on mammary tissue as a result (P <0.01). Testing of telomerase in rat mammary tissue reveals that, aparting from group Ru Pi Xiao, the rest groups and the blank model group, all can decrease the expression of telomerase (P <0.05), further, it is more obvious in tamoxifen group and in the mixed group, which is better than Soothing Liver Qi group and than Regulating Chong and Ren Meridian group (P <0.01).Conclusion: Treatment method of Tonofying kidney and Soothing Liver Qi has significant analgesic effect on rat with HMG, it can improve the symptoms of Kidney deficiency and Liver Qi stagnation to a certain extent, the treatment method has inhibiting effect on rat mammary gland hyperplasia induced by exogenous estrogen and progesterone, it can regulate the sex hormone metabolism in rats, ameliorate the expression and releasing of ER, PR, P53 in mammary tissue, as a result, has therapeutic effect on HMG...
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