007 Chinese patent medicine TianGui Capsules in treating patients with Polycystic Ovary Syndrome Susuana Kuek, Wen-jun

n Wang, Sui-qi Gui Department of Integrated Traditional Chinese and Western Medicine, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011 China Background: Polycystic ovarian syndrome (PCOS) is a complex hormonal disorder and one of the most common reproductive endocrinology abnormalities. The abnormality of hormones secretion of hypothalamus-pituitary-ovarian axis (H-P-O axis) is the main mechanism taking place among the PCOS patients with the result of its complex disorder from which anovulation, hyperandrogenism, metabolic disorder and various pathological abnormalities. Recently, many studies have been published considering Chinese herbal medicine (CHM) as an alternative treatment for women with PCOS so it is worthwhile to analyze and observe the curative effect of traditional Chinese medicine treatment on PCOS. Objective: To evaluate the efficacy and safety of Chinese Patent Medicine TianGui Capsules for women with PCOS, comparing its effects with metformin and Dayin-35 in reducing the level of serum testosterone, ameliorating the anovulation and insulin resistance and transforming the ovary morphosis etc. Design, setting, participants and intervention: 47 outpatients with PCOS from Obstetrics & Gynecology Hospital of Fudan University were randomly divided into 3 groups. The patients in group A (19 cases) were given TianGui Capsules, the patients in group B (17 cases) were given metformin, and the patients in group C (11 cases) were given Dayin-35. 3 groups of patients were treated for 3 months. Main outcome measures: The variation and amelioration of after treatment on serum testosterone (T), sex hormone binding globulin (SHBG), dehydroepiandrosterone sulfate DHEA-S) levels free androgen index (FAI) fasting blood glucose FPG , fasting insulin (FINS , homeostasis model assessment-insulin resistance (HOMA-IR , Insulin sensitive index (ISI) and bilateral ovary volume. Results: After 3 months of treatment among three groups of patient; In group A patients, there were statistically proved significant differences as the serum T and SHBG level, FAI, FINS, and bilateral ovary volume (P<0.05) have decreased, but, serum DHEA-S level (P<0.05) and the FPG level have increased, yet the FPG level had no significant change (P>0.05); In group B patients, there were also statistically proved significant differences as the serum T, SHBG level and left ovary volume (P<0.05) have decreased and the FINS, HOMA-IR were reduced (P<0.01), but, there were also statistically proved significant differences as the serum DHEA-S level and FAI (P<0.05) as well as ISI (P<0.01) have increased. Yet, the FPG level had improved but had no significant change (P>0.05); In group C patients, there also were statistically proved significant differences as the serum T, DHEA-S and bilateral ovary volume (P<0.05) have decreased, but, the serum SHBG level had increased (P<0.01). However, the FPG level had been enhanced but had no significant change (P>0.05). Though the level of serum T among the three groups after the treatment were similar (P>0.05), but in reducing the FAI and increasing the serum SHBG, the result has proved that Group A had better results than Group B, but worse results than Group C; there was no statistically significant difference seen in FINS (P>0.05) before and after treatment among the 3 groups. On the other hand, the insulin sensitivity of Group B has improved. The level of FPG in all 3 groups was evidently increased; but the level of FPG in Group C increased the most. Conclusion: The amelioration of TianGui Capsules on hyperandrogen is not as effective as Dayin-35; but it is better than metformin. The efficacy of TianGui capsules on hvperinsulinemia is not as significant as metformin but perhaps had better outcome than Dayin-35. Chinese patent medicine-TianGui Capsules is a comprehensive treatment for PCOS.

TianGui capsules treat PCOS by regulating the ovarian functions, reducing blood insulin level and transforms the ovary morphosis but not by an inhabitation of the function of H-P-O axis. It is important to do this review as there is currently insufficient evidence about the safety and efficacy of Chinese Patent Medicine for the management of PCOS, a systematic review in this area was warranted. No systematic review on this topic has been done before. The above result is worth further expands the sample size to confirm. Keywords: polycystic ovary syndrome; TianGui Capsules; metformin; Dayin-35

, , , 200011 polycystic ovary syndrome, PCOS -- PCOS PCOS -35 PCOS PCOS PCOS 47 ABC A 19 B 17 C 11 -35 3 3 testosterone,T sex hormone binding globulin,SHBG (dehydroepiandrosterone sulfate,DHEA-S) (free androgen index, FAI) fasting blood glucose ,FPG fasting insulin,FINS hemeostasis model assessment-insulin resistance ,HOMA-IR (Insulin sensitive index, ISI) A TSHBG FAI FINS P<0.05 P<0.05 DHEA-S P<0.05 FPG P>0.05B T SHBG P<0.05FINS HOMA-IR P<0.01ISI P<0.01P<0.05 DHEA-S FAI P<0.05FPG P>0.05C TDHEA-S FAI FINS P<0.05 SHBG P<0.01 P<0.05FPG P>0.05 3 T FAI SHBG A B C FINS B FPG , C FPG -- PCOS PCOS Polycystic ovarian syndrome (PCOS) is an extremely complex syndrome and one of the most common hormonal disorders, affecting 5%to 10% of women of reproductive age [1]. PCOS is characterized by chronic anovulation (ongoing failure or absence of ovulation),

hyperandrogenism (excessive production of androgen in women), dyslipidaemia (lipid metabolism disorder), and is associated with insulin resistance [2] (a reduced glucose response to a given amount of insulin) leading to hyperinsulinaemia(compensatory serum insulin increase). Women with PCOS may present with irregular menstrual cycles, infertility (failure to conceive), hirsutism (excessive hair growth), acne and obesity. The cause of PCOS still remains unclear. It is proposed that high level of androgen in serum appears to be the primary cause. However, insulin resistance and obesity may also trigger the development of this hormonal defect (Gambineri 2006, Alvarez-Blasco 2006, Dunaif 1997).Insulin Resistance causes PCOS by raising insulin levels in the blood stream. Unhealthy lifestyles and genetic conditions can lead to the pancreas overproducing insulin. This excess insulin stimulates the ovaries to produce large amounts of the male hormone-testosterone, which may prevent the ovaries from releasing a follicle each month, thus causing infertility. High levels of insulin also impact the conversion of androgens (male hormones) to estrogens (female hormones), upsetting a delicate balance between the two and having a direct effect on weight gain and the formation of cystic follicles or ovarian cysts[3]. Traditional Chinese Medicine (TCM) pursues an independent theoretical and methodological pathway to review the cause of the disease by implementing the diagnosis and plan for the treatment. Although there is no classification for PCOS within TCM, the symptoms and signs of women with PCOS (Rotterdam 2003 criteria) [4] present can be grouped as two disease classes within TCM- amenorrhea (failure to menstruate) and infertility. Systematic research activities on PCOS in TCM have been carried out since 1980s . The aetiology and clinical characteristics of PCOS still remain controversial but are considered to be related to the disorders of kidneys, liver and spleen. From TCM perspective, reproductive function is being governed by kidneys, as well as gene expression, brain and emotions. It is believed that kidney deficiency may be the main problem in PCOS. TCM is used in treating PCOS by tonifying the kidneys to induce ovulation. Treatment for PCOS is particularly complex. Obstetrics & Gynecology Hospital of Fudan University has conducted a series of clinical and experimental studies of PCOS for 30a. PCOS is a condition occurring due to hormonal imbalances within the body of a woman; Chinese Patent Medicine-TianGui Capsules is developed to treat the condition work by correcting these hormonal imbalances. By correcting the action of H-P-O axis, TianGui Capsules corrects the irregularities in the menstrual cycle of women with PCOS effectively[ 5-6]. This study collected 47 cases of PCOS outpatients in Obstetrics and Gynecology Hospital of Fudan University from November 2008 to December 2009. The purpose of this study was to observe the efficacy of TianGui capsules versus metformin and Dayin-35; to explore whether TianGui Capsules can be served as one of the main drugs for treating PCOS. 1 Materials and methods 1.1 Clinical data A total of 47 PCOS outpatients in Obstetrics & Gynecology Hospital of Fudan University from November 2008 to December 2009 . 1.2 Research methods 1.2.1 Diagnostic and inclusion criteria Based on 2003 European Society of Human Reproduction and Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM) meeting in Rotterdam PCOS diagnostic criteria recommended (2003 Rotterdam diagnosis standard of PCOS)[4]: (1) Irregular ovulation: oligomenorrhea, amenorrhea, or irregular menstrual cycle.

(2) Obvious signs of hyperandrogen or androgen levels rise or anomalies of circulation androgens. (3) Polycystic ovary: ultrasound showed 2-9mm diameter12 follicles of per side ovary or 10cm3 of ovarian volume in 3-5 days of menstruation. Patient with any 2 of the above mentioned symptoms are then confirmed the diagnosis of Polycystic Ovarian Syndrome. 1.2.2 Exclusion criteria (1) Not meeting the diagnostic criteria for PCOS. (2) Other reasons cause hyperandrogenism: late-onset congenital adrenal hyperplasia, Cushing syndrome, androgen secretion of ovarian and adrenal tumors. (3) Hyperprolactinemia, hypothalamic amenorrhea. (4) Thyroid dysfunction. 1.2.3 Medication (1)TianGui Capsule : ShuDi, ZhiMu, YinYangHuo, HuangJing, DangGui, TaoRen, ShiChangPu, GuiBan, BuGuZhi, HuZhang and MaBianCao;a hospital prescription which approved by Shanghai Food and Drug Administration, produced by Cai Tong De Shanghai Pharmaceutical Co., Ltd. The licensed number of TianGui Capsules is YZ090087. (2)Metformin: Metformin Hydrochloride Enteric-coated Tablets hydrochloride produced by Bristol-Myers Squibb.The license number of metformin is BX20000396. (3) Dayin-35: Ethinylestradiol and Cyproterone Acetate Tablets, Compoundcyproterone acetate tablet produced by Bayer (China) Limited Co., Ltd The licensed number of Dayin-35 is J20040104(2001)J-70);The registered number for imported drugs of Dayin-35 is H20070384. 1.2.4 Grouping and treatment The 47 patients were randomly assigned to Group A (Tian Gui Capsules group), Group B (Metformin group) and Group C (Dayin -35 group) 3 groups after they have signed the consent. Group A (19 cases): 6 tablets of Tian Gui Capsule 3 times daily, taken for 3 months. Group B (17 cases): 500mg, 2 times daily, taken for 3 months. Group C (11 cases): 1 tablet of Dayin-35 per day on the 5th day of menstruation or withdrawal bleeding for a period of 21 days, taken for 3 cycles of menstruation Patients from Group A and Group B who faced amenorrhea within 60 d during treatment were given 10 mg per time daily of Medroxyprogestrone Acetate for a total of 5 d to induce menstruation. 1.2.5 Methods and Efficacy evaluation index a. Fill-up observation form b. Anthropometry: measure waist circumference, weight, WHR (waist-hip ratio) and calculate BMI (body mass index) according to the World Health Organization measurement standard. c. Hormone determination: determine the level of serum FSH(follicle stimulating hormone), serum LH(luteinizing hormone), serum E2(estrogen), serum T (testosterone), serum DHEA-S (dehydroepiandrosterone sulfate) by CLIA (chemiluminesence immuno assay) and the level of serum SHBG(sex hormone binding globulin) by ELISA (enzyme-linked immunosorbent assay) on the progesterone withdrawal bleeding or 3 to 5 day of menstruation before treatment. The main efficacy evaluation index for the treatment are serum T and serum SHBG, the level decrease of these 2 serums can be shown as hyperandrogen has been improved. d. Blood biochemistry measurement: FPG (fasting glucose) (by glucose oxidase method), FINS (fasting insulin) (by CLIA), and calculate FAI (free androgen index, T (mmol / L) x100/SHBG (mmol / L)) to assess the level of biological activity of androgens. Calculate HOMA-IR (homeostasis model insulin resistance index, FINS (mIu / L) * FPG (mmol / L) / 22.5, 1.66 mean insulin resistance) and insulin sensitivity index (ISI, 1 / (FINS* FPG), <0.021 mean the reduced susceptibility), as the assessment of hyperinsulinemia, insulin resistance and abnormal glucose metabolism status.

e. Ultrasound monitoring: calculate the follicles of each side ovary and measure the follicle size and each side ovarian volume by the vaginal or rectum with the three-dimensional Doppler. The decrease of the ovarian volume confirms the fact that the function and morphosis of ovary have been improved and transformed. After 3 months treatment, re-measure and retest the aforementioned. (Chart 1)
create a random table determine diagnosis and exclusion criteria devise treatment plan prepare informed consent

Patients

1. Check 2. Blood test 3. Ultra scan 4. Diagnosis Excluded

1. Coincide with diagnosis 2. Consent 3. devide into treatment group according to the random table Group A

Group B

Group C

1. After 3 months treatment,

re-measure and retest the aforementioned which had devised 2. Statistical all the data

Chart 1Technical flow 1.3 Statistical analysis Data analyzed with SPSS 11.5 software, and resulted in X s. Before and after treatment within each group were compared with paired t tests. Among the 3 groups after treatment were compared with ANOVA. Fisher exact prohibition was used to compare rate. 2 Results 2.1 Baseline data 47 outpatients were aged from 15 to 40 years old, 4 cases of unmarried, 43 cases of married;2 cases of fertilized, infertility in 41 cases, accounting for 95.35% (41 / 43).The differences of body weight and WHR between 3 groups before treatment were not significant (P> 0.05), and were comparable. The comparison of body weight, BMI and WHR within before and after treatment of Group A and Group B were declined, Group C was the only group which the weight and BMI had an increase tendency after treatment (Table 1). Table 1 General situation of each group Xs
Group A N 19 heightm 1.590.03 Weight (kg) 59.478.76 58.578.37* BMIkg/m2 23.263.34 22.903.09* WHR 0.830.04 0.820.08

B C

17 11

1.580.05 1.580.02

64.557.77 61.466.90* 58.8610.66 59.0410.18*

25.702.96 24.612.87* 19.2710.46 19.4510.46*

0.830.05 0.820.05 0.830.07 0.820.08

A: TianGui group; B: Metformin group; C: Dayin-35 group. *P<0.05, vs. before treatment 2.2 Comparison of laboratory tests and ovarian volume within 3 groups 2.2.1 Hormone Before treatment, the levels of serum T, DHEA-S, SHBG and FAI did not have significant differences (P>0.05) among the 3 groups and were comparable. After treatment: (1) Comparison on the reduction of the serum T level among the 3 groups had no difference (P>0.05). (2) Group C was the only group that the serum SHBG level had increased (P<0.01) and the serum DHEA-S level had decreased (P<0.05). (4) Group B was the only group that the FAI had increased (P<0.01). (Table2, Table 3 & Table 4) 2.2.2 Glucose metabolism Before treatment, differences of the FPG and the ISI have no significant (P>0.05) among 3 groups and were comparable; but the FINS and HOMA-IR among 3 groups were statistically significant (P<0.05) and incomparable. Therefore, comparing the D-value (difference value of before and after treatment in each group) of FINS and HOMA-IR among 3 groups have no difference (P>0.05) and were comparable. After treatment: (1) Comparison of FPG level among the 3 groups had no difference (P>0.05), yet each group had an increase tendency while Group C had increased the most. (2) Comparison of ISI among the 3 groups was similar (P>0.05) while Group B was the only group that the insulin sensitivity had increased (P<0.01). (4) Comparison of the D-value (difference value ) in FINS and HOMA-IR among 3 groups had no difference (P>0.05), showed that function to reduce FINS level and HOMA-IR of 3 groups was similar. (Table 3 & Table 4) 2.2.3 Ovarian volume before treatment, bilateral ovarian volume among 3 groups have no difference (P>0.05) and were comparable. After treatment: (1) Compared to the left ovarian volume between Group A and Group C, the difference was statistically significant (P<0.05). (2)Compared to the right ovary volume between Group A and Group C, the difference was statistically significant (P<0.05). To decrease or reduce the ovarian volume, Group C was better than Group A and Group B. Group B was the only group with an increase tendency of the right ovary. (Table 5). 2.3 Comparison of laboratory parameters and ovarian volume between before and after treatment in each group (1) Group A: serum T, SHBG levels and FAI were reduced (P<0.05). Level of FINS were reduced (P<0.05). Bilateral ovarian volume were reduced (P<0.05). (2) Group B: serum LH, T and SHBG levels were reduced (P<0.05). Left ovarian volume were reduced (P<0.05). Levels of FINS and HOMA-IR were reduced (P<0.01). FAI and ISI were increased (P<0.01) (P<0.05) while right ovarian volume had an increase tendency. (3) Group C: Serum LH, T, DHEA-S levels were reduced (P<0.05). Level of FINS were reduced (P<0.05). Bilateral ovarian volume were reduced (P<0.01). Serum SHBG level have increased (P<0.01) while level of FPG have an increase tendency. (Table2, Table 3 & Table 4) Table 2 Sexual hormone level of each group
Group

Xs A: TianGui group; B: Metformin group; C: Dayin-35 group.*P<0.05, vs. before treatment;

n FSH IU/L 6.471.33 6.531.36 7.541.98 7.141.59 8.272.64 7.083.39 LH IU/L 9.035.05 9.497.19 9.794.88 8.485.22 11.404.00 5.452.74* E2 pmol/L 138.8876.71 146.2280.02* T nmol/L 2.060.53 1.940.50* DHEA-S umol/L 5.521.94 6.251.86* 6.982.18 7.462.32* 4.571.89 4.191.43*

A(before treatment) 19 A(3mth treatment) 19 B(before treatment) 17 B(3mth treatment) 17 C(before treatment) 11 C(3 mth treatment) 11

157.1665.02 172.26130.10* 164.4852.77 175.8269.00*

2.30.0.59 1.97 0.47* 2.19.0.80 1.630.43*

SHBG nmol/ml 64.7446.46 56.1729.81* 61.7522.15 60.3040.85* 73.1545.22 258.02101** 6

Table 3 Glyco Metabolism indexes of each group Xs

Group A(before treatment) A(after treatment) B(before treatment) B(after treatment) C(before treatment) C(after treatment) n 19 19 17 17 11 11 FPG mmol/L 4.25 0.39 4.36 0.40 4.47 0.45 4.570.45 4.280.36 4.650.26 FINS IU/L 11.367.37 10.74 6.04* 14.604.35 12.61 8.38** 12.018.81 9.994.51* HOMA-IR 0.46 0.96 0.49 0.87 1.010.33 0.740.66** 0.640.60 0.510.56 ISI 0.05 0.10 0.05 0.10 0.010.05 0.020.01** 0.020.01 0.020.01 FAI 4.833.27 4.683.08* 4.833.83 5.194.85** 3.791.77 0.77.55**

A: TianGui group; B: Metformin group; C: Dayin-35 group.*P<0.05, vs. before treatment;**P<0.01, vs. before treatment; P<0.05, vs. group A; P<0.05, vs group B; P<0.05, vs. group C Table 4 D-value difference value of before and after treatment in each group of FINS and HOMA-IR in each group Xs
Group A B C N 19 17 11 FINS IU/L -0.625.76 -2.197.87 -2.016.92 HOMA-IR 0.030.52 -0.290.61 -0.020.33

A: TianGui group; B: Metformin group; C: Dayin-35 group. Table 5 Ovary volume of each group Xs
Group A (before treatment) A (after treatment) B(before treatment) B (after treatment) C(before treatment) C (after treatment) N 19 19 17 17 11 11 Left ovary volume cm3 11.424.24 9.024.00* 10.244.33 9.964.07* 11.183.31 8.903.59** Right ovary volume cm3 12.173.71 11.794.41* 12.236.99 12.434.36 13.715.75 10.244.65**

A: TianGui group; B: Metformin group; C: Dayin-35 group.*P<0.05, vs before treatment;**P<0.01, vs before treatment. P<0.05, vs. Group A. 3 Discussion 3.1 The influence of TianGui Capsules on the endocrine of PCOS patients <SuWenTreatise on the Natural Truth in Ancient Times> pointed: "when a girl is 7 year-old, the emanations of kidneys (kidney-qi) become abundant, she begins to change her teeth and her hair grows longer. When she is 14 year-old, the kidney-essence which promotes the reproductive function is abundant and her Chong and Ren Meridians begin to activate and become stronger, she begins to have menstruation and is able to conceive, ... ...[7] these indicate that once those several physiological conditions are matured, girls begin their menstruation which is generated and formatted under the cooperation between the kidney-qi the kidney-essence the Chong and Ren Meridians- uterus axis. Water is governed by the Kidney-qi, once kidney-qi is insufficient and causes water retention and leads to metabolic disorders that will transform into phlegm. Therefore, the failure of kidney-qi can be considered as the main reason of phlegm formation. Besides, according to the theory of TCM,Blood stagnation is not only due to phlegm as the cause ,yet both of them could be of parallel from same starting point of pathological mechanisms therefore these
7

two pathologically conditions will lead to the disharmony of Chong and Ren Meridians and will transform into heat which may impair yin if such conditions persisting . [8] Based on the above theory, kidney-qi and kidney-yin deficiency is directly related to PCOS. However, since PCOS patient's H-P-O axis functions abnormally [2-3] with metabolic disorders from which hyperandogenism and insulin resistance are manifested, the cause of hyperandogenism and insulin resistance is possibly due to kidney deficiency. Based on the test results by the Obstetrics and Gynecology Hospital of Fudan University, Lirong Zhou [6] and others who have prescribed Traditional Chinese prescription-TianGui for yin-nourishing, heat-clearing and blood circulation-quickening to treat PCOS with hyperandrogen was effective. Yang Shu-Ping et al [9], Yu Jin, etc. [10] and Yue-Ping Zhang et al [11] reported that applying the hyperandrogen, hyperinsulinemia and anovulatory rats with TianGui prescription-a prescription for tonifying kidney-yin, the rats hyperinsulinemia and hyperandrogenism conditions were improved significantly. According to those studies, prescription of TianGui has been introduced into a patent medicine and has been widely used as PCOS medication. Although the safety and the mechanism of Yin-nourishing and clearing-heat drugs-TianGui Capsules in treating patients with PCOS is still unclear ,in this study, 19 PCOS patients of Group A were treated by TianGui Capsules after 3 months showed that the hyperandrogen symptoms had improved which with a significantly lower T level (P<0.05) and a lower FINS level (P<0.05).Even though HOMA-IR and ISI of Group A patients had no difference (P> 0.05), yet the amount of insulin insensitive and insulin resistance in patients were reduced, moreover, some patients with different degrees of skin pigmentation or Acanthosis nigrans which is caused by hyper secretion of insulin and androgen were receded and the elasticity of their skin had been enhanced after treatment. These outcomes showed that TianGui Capsules treated hyperinsulinemia and insulin resistance effectively as it assists in reducing the functions of serum T and insulin levels. Moreover, the bilateral ovarian volume of Group A patients had decreased (P<0.05) while level of serum LH and FSH were not inhibited, at the same time, the FAI of group As patients had reduced after treatment, once again these results confirmed that TianGui Capsules not only has the effect of reducing androgen and insulin levels by not inhibiting H-P-O axis; but can be used to change ovarian morphologic through amelioration in the micro-environment of ovary and its effects in reducing androgen levels was better than metformin.Beside, during the post treatment follow up, most patients had no complained about any gastrointestinal upset, and patients with constipation problem had improved ,these feedbacks showed and confirmed that the ingredients of yin-nourishing and heat-clearing drugs TianGui Capsules are suitable and applicable in treating the PCOS patients with yin-deficiency and internal-heat .Perhaps the effect will be more obvious if the treatment can be prolonged. Due to the short-term medication and inadequate amount of the samples, the function to reduce serum LH and DHEA-S was not noticeable. 3.2 The influence of Metformin on the endocrine of PCOS patients Metformin is a biguanide as an insulin sensitizer by inhibiting intestinal absorption of glucose, gluconeogenesis from glycogen and promoting anaerobic glycolysis of sugar to increase the extrinsic muscle tissue glucose uptake and utilization. Metformin also increases tissue sensitivity to insulin, reduce insulin resistance which is caused by hyperinsulinemia and hyperandrogenism, and to correct the disorder of lipid metabolism, improve menstrual disorders, spontaneous ovulation induction [10][11][12]. In this study, 17 PCOS patients of Group B were treated by metformin after 3 months showed that the hyperandrogen and

hyperinsulinaemia symptoms were improved which with a significantly lower serum T level(P<0.05),a lower FINS level (P<0.01) ,a lower HOMA-IR (P<0.01)and a higher ISI (P<0.05) than before treatment. At the same time, signs of acne and hirsutism were improved. Nevertheless, the right ovarian volume and the FAI were increased, these results showed and speculated that metformin reduced the androgen levels by adjusting the abnormal of insulin metabolism.Besides, during the post treatment follow up, most patients complained about gastrointestinal upset, diarrhea, and other side effects ,these feedbacks may showed that metformin is unsuitable treated as a long-term medication for PCOS . 3.3 The influence of Dayin-35 in the endocrine for PCOS patients Dayin-35 is a short term oral contraceptives, each containing 2mg cyproterone acetate (CPA) and 35ug ethinyl estradiol [13]. CPA which has a strong and effective anti-androgen and progestin activity can inhibit secretion of pituitary gonadotropin, especially the secretion of serum LH, testosterone and dihydrotestosterone, competitive inhibition of androgen receptor, thereby ovarian source androgens secretion can be reduced [14], and the CPA and ethinyl estradiol mixture can increase the liver synthesized serum SHBG. Thus free testosterone decreased [15] can alleviate and improve those hyperandrogenism signs effectively such as acne and hirsutism; it can also regulate the menstruation and use as endometrial hyperplasia prevention [14-15]. In this study,11 PCOS patients of Group C were treated 3 cycles treatment of Dayin-35 showed that signs of acne, hirsutism and other signs of hyperandrogen had improved which with a significantly lower serum T and DHEA-S levels (P<0.05),a higher serum SHBG level (P<0.01), a lower FINS level (P<0.05), a HOMA-IR reduced tendency and a ISI increases tendency than before treatment. Besides, due to its effective reduction of serum LH level and renal source androgens, the bilateral ovarian volume (P<0.01) had significantly reduced. These results showed and confirmed that the mechanism of Dayin-35 in treating patients with PCOS is to restrain and inhibit the H-P-O axis function. However, during and after the course of treatment, patients body weight, BMI and FPG were increased and the FPG increased rate in this group is most obvious, moreover, during the post treatment follow up, most of the patients complained about breast pain, gastrointestinal upset, weight gain and other side effects. These indicated and showed that Dayin-35 is not good at improving the glucose metabolisms of PCOS; but whether a long-term use of Dayin-35 may lead to increase of blood sugar levels in patients with PCOS and will causes other side effects, is still required a further investigation. Therefore as a conclusion and speculation as well ,as long as treatment of PCOS concerned the role of metformin is more focus for adjusting the abnormalities of insulin metabolism, while Dayin-35 is to restrain the H-P-O axis function; but only TianGui Capsule improves the menstruation cycles, ovarian function and metabolic abnormalities without inhibiting H-P-O axis .Even though the pharmacology and mechanism of this Chinese patent medicine is still unsure and incomplete, further studies are required to ensure its mechanism and to confirm whether other medication or drugs should be used together that might improve ovulation , lowering blood insulin level and increasing serum SHBG level, yet, the medication for PCOS by kidneys yin-nourishing and heat-clearing drugs TianGui Capsules is diversified and can be used as a long-term treatment for PCOS patients.

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 2009:38(11) 2. Diamanti K E , Kouli C R , Bergiele A T , et al . A survey of the polycystic ovary syndrome in the Greek island of Lesbos: hormonal and metabolic profile. J Clin Endocrinal Metab ,1999 Nov;84(11) :4006-11. [PubMed] http://www.ncbi.nlm.nih.gov/pubmed?term=Diamanti K E %2C Kouli C R %2C Bergiele A T %2C et al A survey of the polycystic ovary syndrome in the Greek island of Lesbos %3Ahormonal and metabolic profile. J Clin Endocrinal Metab %2C1999 %2C84 %3A400624011 3. Li MZH. Diagnosis and therapy of the polycystic ovary syndrome. Chin Obste Gynecol. 2002; 37 (7): 444~446.Chinese 200237(7)444~446. 4. Ricardo Azziz .Diagnosis of Polycystic Ovarian Syndrome: The Rotterdam Criteria Are Premature. The Journal of Clinical Endocrinology & Metabolism March 1, 2006 vol. 91 no. 3 781-785 . http://jcem.endojournals.org/content/91/3/781.full 5. Wei MJ, Clinic observation of TianGui Capsules in treating anovulation, hyperandrogenism and menstruual disorder. [J] Chinese Journal of Endocrinology and Metabolism. 2001 17(2):105.Chinese . 200117(2):105 6. Zhou LR, Yu J. Clinical observation of treatment of hyperinsulinemia, hyperandrogen and anovulation by invigorating kidney YIN.Chinese Journal of intergrated Traditional and Western Medicine.1996;16(9):515~518. Chinese 96,16(9) 7.Ilza Veith. Huang Ti Nei Ching Su Wen-The Yellow Emperors Classic of Internal Medicine.Pg 98-99 ISBN 967-978-429-0 8. Wang XJ, Shen ZY.Treatment with nourishing YIN for lowering pathogenic fire of the polycystic ovary syndrome. Shanghai Journal of Traditional Chinese Medicine.1999;33(12):22~23. Chinese , . 1999 33(12)22~23. 9. Yang SP, Yu J, Zhuang LZ. The function of the chinese invigoration kidney medicine on pituitary, ovary and adrenal gland of infertile rats.Chinese Journal of intergrated Traditional and Western Medicine.1993;13(Theory research set):319~321.Chinese ,,. 199313()319~321. 10. Yu J, Sun YL, Shao GQ, et al. The regulation of hypothalamus-pituitary-ovary in polycystic ovary syndrome by invigorating kidney and eliminating phlegm. Chinese Journal of intergrated Traditional and Western Medicine.1986; 6 (4): 218~221.Chinese ,, -- 198664218~221. 11. Zhang YP, Yu J, Gui SQ. The pathogenesis in androgen caused infertile rats and the function of Chinese nourish YIN medicine in acceleration of ovulation. Chinese Journal of Endocrinology and Metabolism.1994;10(2):98~101.Chinese ,, . 199410298~101. 12. Li GH, Huang W .Application of metformin in polycystic ovary syndrome.Journal of Practical Obstetric and Gynecology.2005;21(9):534~536.Chinese

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 J 200521(9) 534~536. 13. Julie L. Sharpless.Polycystic ovary syndrome and the metabolic syndrome. Clin Diab 20032(1)154. [CLINICAL DIABETES] http://clinical.diabetesjournals.org/content/21/4/154.full 14. Xia DF, Hua K.The role of metformin in polycystic ovary syndrome. [J] Guo Wai Yi Xue Fu Chan Ke Xue Fen Ce. 2004;31(2):73~76.Chinese ,. PCOS [J]. 200431 (2): 73~76. 15. Zhang MY. Infertility and Reproductive Endocrinology. 2th ed. Beijing:.2005:97~102. Chinese .. 2 . :. 200597102. 16. Han XM, Jiang K.35 cases clinical observation of Dayin-35 of the polycystic ovary syndrome. Occupation and Health;2007;12(23):222. Chinese , -35 30 200712(23):222. 17. Livingstone C, Collison M. Sex steroids and insulin resistance. Clin Sci (London), 2002, 102 (2): 151~166. [PubMed] http://www.ncbi.nlm.nih.gov/pubmed?term=Livingstone C%2C Collison M. Sex steroids and insulin resistance. Clin Sci (London)%2C 2002%2C 102 (2)%3A 151~166. For enquiries, please call 1. Prof Wen-jun WANG Tel: (M) 13818607938 021-63451200 Add: Fudan University, Department of Integrated Traditional Chinese and Western Medicine, Obstetrics and Gynecology 419, Fangxie Road Huangpu, Shanghai, China 419 200011 Email: wjwwang@yahoo.com.cn 2. Prof Sui-qi GUI Tel: (M) 13817632079 Add: Fudan University, Department of Integrated Traditional Chinese and Western Medicine, Obstetrics and Gynecology 419, Fangxie Road Huangpu, Shanghai, China 419 200011 Email: sqgui@hotmail.com

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