| Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age. The prevalence of this disease is about5-10%. PCOS is characterized by combination of oligo/amenorrhoea, clinical or endocrine signs of hyperandrogenaemia and polycystic ovaries. Most of the patients with PCOS are disturbed by infertility, menstrual disorder, obesity, hirsutism, acne and so on. The condition of sustainable development of PCOS is associated with increased chances for cardiovascular disease, diabetes and endometrial cancer. There are many further researches about PCOS after it’s first described in1935.Burghen put forward the involvement of insulin resistance in the pathogenesis of PCOS for the first time in1980. The resent studies of PCOS and insulin resistance confirmed that insulin resistance is a key in the pathophysiology of PCOS. About65%-70%PCOS patients have insulin resistance. But, up to present times, there are no unified views on the effect of insulin resistane on the reproduction functions, such as ovulation, pregnancy, and the effect of metformin on improvement of these reproduction functions. There are studies that demonstrate insulin sensitizer like metformin could increase ovulation and pregnancy rates. But some other researches reported that metformin had no effect on the metabolic and reproduction functions of PCOS patients. It was demonstrated that the expression of molecules associated with endometrial receptivity decreased in PCOS patients. However, there are little researches about whether insulin affects the expression of molecules associated with endometrial receptivity.This study searched randomized controlled trails (RCTs) of the treatment of PCOS in published studies and conducted a systematic review and meta-analysis in order to investigate the effect of insulin sensitizer on ovulation and pregnancy outcomes in patients with PCOS, Also analyzed are the clinical data of PCOS patients to find out the factors that affects the outcomes of fertility regulation in PCOS patients. Moreover, this study investigated the treatment of insulin sensitizer combined with anti-androgen drug to find out the best treatment of PCOS patients. The expression of molecules for endometrial receptivity in different concentration of insulin in vitro experiment was also recorded in order to acquire the regulation effect of insulin on endometrial receptivity. This study breaks down into four parts, evenly distributed toward the goals stated above. The following chapters provide more detailed description of what was done in each part.Part OneEffect of insulin sensitizer on ovulation and reproduction outcomes in women with PCOS:a Meta-analysis of randomized controlled trialsObjective:To evaluate the effect of MET administration on ovulation and reproduction outcomes in patients with PCOS.Methods:Meta-analysis of available data from RCTs that examined the ovulation, pregnancy and live birth rate after the administration of clomiphene citrate (CC) or MET alone or combined. The search was performed at such bibliographic databases as Medline, Embase and Science Direct before2012. The key words for search were as follows:PCOS, polycystic ovary syndrome, metformin, clomiphene citrate, ovulation induction, pregnancy, randomized controlled trial.Results:Seventy-one RCTs were identified and screened,55were excluded. The ovulation rate was found to be higher in the group treated with MET combined with Clomiphene citrate (CC) than one with CC, odds ratio (OR):1.27,95%confidence interval (95%CI)(1.03-1.56), while the pregnancy and live birth rate showed no significant difference between the two groups, OR:1.19,95%CI (0.99-1.42) and OR:0.99,95%CI (0.84-1.17), respectively. The MET+CC group produced a higher ovulation and pregnancy rate than MET group, OR:2.10,95%CI (1.89-2.34) and OR:2.08,95%CI (1.55-2.80), respectively, while between two groups the live birth rate showed no significant difference, OR:1.50,95%CI (0.75-3.00). The ovulation rate was lower in MET than in CC group, OR:0.65,95%CI (0.43-0.995), while between the two groups the pregnancy and live birth rate showed no significant difference, OR:0.86,95%CI (0.42-1.74) and OR:0.89,95%CI (0.71-1.13).Conclusion:The current study indicates that combination of MET and CC could gain advantage over a single administration in the ovulation induction and pregnancy rate, which is an indirect evidence of insulin resistance that affected fertility outcomes in patients with PCOS.Part TwoStudy of the effect of insulin on the outcomes of fertility regulation and the intervention measurementsObjective:1. Analyze the factors of PCOS influencing the ovulation induction sensitivity2. Evaluate the administration effect of insulin sensitizer combined with anti-androgen on the ovulation and reproduction outcomes in patients with PCOS.Methods:1. Anovulation PCOS patients in the process of ovulation induction were recruited as the research subjects. Then the study compared their body compositions, hormonal and metabolic parameters, and analyzed the correlation between body composition, hormonal, metabolic features and the ovulation induction sensitivity2.Anovulation PCOS patients were separated into three randomized groups, and were treated with CPA/EE, MET or combined, respectively for three cycles. Upon finishing the treatment, the study compared the changes of the body composition, hormonal, metabolic features, performed the ovulation induction and investigated the effect of treatment on ovulation and pregnancy.Results:1. Ovulation induction sensitivity was significantly related to TT, FAI, SHBG, LH, DHEA-S, INS30, INS60, IAUC, GAUC.2. INS30, INS60, IAUC and GAUC were independently related to ovulation induction sensitivity from TT, FAI, SHBG, LH, DHEA-S (P<0.05).3. After three months treatment, the body weight and BMI decreased in MET and MET+CPA/EE groups with statistically significant difference (P<0.05). The level of decrease of BMI and body weight had no statistical difference on MET and MET+CPA/EE groups (P<0.05), and there was no significant difference in the change of WHR before and after treatment among three groups. The differences of body weight, BMI and WHR had no statistical significance in CPA/EE group.4. After three months’treatment, significant decreases of INS30’, INS60’, GAUC appeared in MET+CPA/EE and MET groups (P<0.05), and the level of decrease had no significant difference between MET+CPA/EE and MET groups; there was no significant difference in MET+CPA/EE group while comparing the values of fasting insulin (INS0’), IAUC, fasting plasma glucose (GLU30’),GLU30’, GLU60’, HOMA-IR (P<0.05). The levels of INSO’, IAUC, GLUO’, HOMA-IR decreased significantly after treatment in MET group (P<0.05). The values of GLUO’, GLU30’, GLU60’, GAUC increased after the treatment of CPA/EE (P<0.05), while the values of HOMA-IR, IAUC, GAUC, INS0’had the tendency to increase with no significant difference (P<0.05).5. The decreases of LH, LH/FSH, T, DHEA-S, FAI and the increase of SHBG had significant differences in MET+CPA/EE and CPA/EE group (P<0.05), and the decrease of LH/FSH in CPA/EE group was higher than that in MET+CPA/EE group (P<0.05), while the changes of LH, T, DHEA-S, FAI and SHBG had no significant differences between MET+CPA/EE and CPA/EE group (P<0.05). The decrease of LH/FSH, T, FAI in MET group had statistical difference between before and after treatment (P<0.05), but the level of decrease was lower than MET+CPA/EE and CPA/EET group (P<0.05); the change of DHEA-S had no significant difference in MET group before and after treatmeng (P<0.05). There was no difference of FSH among the three groups (P<0.05).6. The ovulation and pregnancy rates were higher in MET+CPA/EE group than in CPA/EE group, and the time to HCG day was shorter in MET+CPA/EE group than in CPA/EE group or MET group (P<0.05). The ovulation rate was higher in MET+CPA/EE group than MET group significantly (P<0.05), while the pregnant rate was higher in MET+CPA/EE group than MET group but there was no statistical difference between two groups (P=0.077).Conclusion:1. Indexes of androgen and insulin were related to the sensitivity of CC in induction ovulation. Insulin was the independent risk factor of inducing ovulation.2. The insulin sensitizer therapy combined with anti-androgen adminstration could improve patients’ condition.3. The combined pretreatment of insulin sensitizers and anti-androgen drug could increase the ovulation induction sensitivity of CC, improve the pregnancy rate, and shorten the time to reach maturation of follicle. Part Three Important value of sex hormone binding globulin in the assessment of glucose metabolism in Chinese women with PCOSObjective:To investigate the value of sex hormone binding globulin in the assessment of glucose metabolism in PCOS patients.Methods:Prospective clinical study of282PCOS Chinese women, Serum SHBG levels, body composition, hormonal and metabolic features and insulin sensitivity indices were evaluated at baseline. The patients were divided into two groups according to the low quartile of SHBG (group1:low level of SHBG group, SHBG<20.4; group2:SHBG>20.4). Compare the defference between groups with body composition, hormonal and metabolic features and insulin sensitivity indices; Compare the difference of the levels of SHBG among normal glucose PCOS patients, IGT PCOS patients and DM PCOS women; Compare the difference of the levels of SHBG between IR and non-IR POCS women. Analyse the relationships between SHBG and metabolic parameters. Assess the value of SHBG in the assessment of glucose metabolism by ROC analyses.Results:There were no significant differences between groups in ages, height, acne scores, TC, TG, HDL, LDL, FSH, LH, PRL, E2, TT, while there were significant differences between groups in weight, BMI, waist cercumferences, WHR, Ferriman-Gallwey scores, Acanthosis nigricans, fasting glucose,2h postprandial glucose, fasting insulin,2h postprandial insulin, HOMA-IR, GAUC, IAUC, SHBG, FAI, DHEA-S (P<0.05). Incidence of IGT, DM, overweight, insulin resistance (IR) in the lower SHBG group was higher than the rest (32%vs17.4%,38.6%vs1.0%,59.1%vs33.3%,100%vs67.1%, P<0.05). The SHBG level was significantly different among normal glucose PCOS patients, IGT PCOS patients and DM PCOS patients (44.33±33.71nmol/L,26.88±22.15nmol/L,13.97±5.60nmol/L, respectively), and the SHBG level was significantly higher in IR-PCOS patients than in non-IR PCOS patients (32.89±3.29nmol/L,51.87±7.13nmol/L, respectively)(P<0.05). There were negative correlations between SHBG and fasting glucose (r=-0.229; P<0.05),2h postprandial glucose (r=-0.476; P<0.001), fasting insulin(r=-0.457; P<0.001),2h Postprandial insulin (r=-0.428; P<0.001), HOMA-IR(r=-0.456; P<0.001), GAUC (r=-0.407; P<0.001), IAUC(r=-0.413; P<0.001). Receiver operating characteristic analysis showed SHBG [area under the curve (AUC):0.929,95%CI:0.86-0.997] had the same assessment value of DM in PCOS women as HOMA-IR (AUC:0.984,95%CI:0.841-0.995) and free androgen index (FAI)(AUC:0.897,95%CI:0.803-0.991), while be superior to body mass index (BMI)(AUC:0.785,95%CI:0.696-0.874) and T (AUC:0.655,95%CI:0.457-0.852)(PO.05). On assessment of IGT in women with PCOS, SHBG (AUC:0.736,95%CI:0.64-0.83), BMI (AUC:0.733,95%CI:0.644-0.822), FAI (AUC:0.733,95%CI:0.636-0.833) and HOMA-IR (AUC:0.777,95%CI:0.688-0.866) had equal effect, while be superior to T (AUC:0.5965,95%CI:0.486-0.707)(P<0.05). On assessment of IR in women with PCOS, SHBG (AUC=0.745,95%CI:0.6802-0.80976), BMI (AUC=0.7878,95%CI:0.72233-0.85323), FAI (AUC=0.7355,95%CI:0.67482-0.79626) had equal effect, while be superior to T (AUC=0.5587,95%CI:0.48196-0.63551).Conclusion:SHBG has important value in the assessment of glucose metabolism and could be an effective and convenient diagnosis parameter for IR, IGT and DM with PCOS women.Part FourThe effect of insulin resistance on the endometrial receptivityObjective:To investigate the influence of insulin on the expression of molecules related to endometrial receptivity.Methods:Cultured endometrial epithelial cells in vitro (primary cultured endometrial glandular epithelial cells or Ishikawa cells) were processed by different concentrations of insulin, and the combination of different concentrations of sugar or androgen with each concentration of insulin was used to process endometrial epithelial cells. The expression of integrinαVβ3and osteopontin (molecules related to endometrial receptivity) were detected by Real-time PCR, Western blot.Results:The expression of integrin a Vβ3/OPN was highest in30mIU/L concentration of insulin. When in100mIU/L, the expression of integrin a V p3decreased statistical significantly comparing to tht of10mIU/L and30mIU/L (P<0.05). In high glucose combined with the insulin concentration of30mmol/L group, the expression of integrinβ3protein was reduced significantly comparing to10mIU/L group (P<0.05); in each concentration of androgen group, the expression of ITGβ3 was lowest in100mlU/L insulin group; the presence of the expression of integrin β3protein was the highest in10mIU/L, while the expression of ITGβ3in30mIU/L insulin concentration dropped obviously with statistically significant differences comparing with that of10mIU/L (P<0.05). In androgen concentration of10"7M, there was very low level of expression of ITGβ3.Conclusion:Physiological concentration of insulin was benefitial for the expression of molecules related to endometrial receptivity. The high concentration of insulin down-regulated the expression of key molecules for endometrial receptivity including integrin and OPN, suggesting that high concentration of insulin could hinder the establishment of endometrial receptivity. High levels of glucose and insulin could coordinately down-regulate endometrial receptivity molecule. High concentrations of androgens also down-regulate the expression of molecules for endometrial receptivity. High androgen and high insulin may cause synergistic damage on endometrial receptivity. Therefore, the results suggested that intervention by decreasing insulin and androgen woud enhance the expression of the molecule endometrial receptivity, help to improve the pregnancy rate, and reduce the abortion rate for PCOS women. |
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