Clinical Study Of Insulin Sensitizer Combined With Diane-35 In Treating Of Polycystic Ovary Syndrome

【Background】Polycystic ovary syndrome(PCOS) is a very common and complex endocrine disease that affects 6%to 10%of women in reproductive age life.It is a heterogeneous condition characterized by chronic anovulation,irregular menses and infertility,and symptoms of androgen excess,such as hirsutism and ache.In the long term,it increase the risk of type 2 diabetes,coronary heart disease,hypertensive disease,hyperlipidemia and other metabolic complications,and endometrial carcinoma.It seriously affects the reproductive function and physical and mental health.Although it's mechanism entirely remains unclear,hyperinsulinemia and hyperandrogen may be two important foundations of pathophysiology.More than half of patients with PCOS suffer with insulin resistance,affecting approximately 50-60%,whether obesity or not.By improving insulin sensitivity and controlling hyperandrogenism,we may treat patients with PCOS.It is reported that chronic inflammation was characteristic of type 2 diabetes and cardiovascular diseases,and plasma inflammatory factors were recognized as risk factors for IR.TNFαis one of inflammatory factors,extensive research has highlighted several potential mechanisms by which TNFαinduces insulin resistance. These include:inhibited insulin signal transduction,and accelerated lipolysis and a concomitant increase in circulating FFA concentrations.In recent years,some scholars have found that PCOS also is a chronic low-grade inflammatory state,the IR may be associated with TNFα,IL-6,CRP and other inflammatory factors.So TNFαhas become a cytokines concerned of patients with PCOS.Metformin is a biguanide insulin sensitizer,it is considered an insulin sensitizer since it lowers glucose levels without increasing insulin secretion.In fact,it lowers hepatic glucose production by reducing gluconeogenesis and by decreasing glycogenolysis,increases peripheral glucose uptake by skeletal muscle and adipose tissue,and reduces intestinal glucose absorption.Pioglitazone is one of the insulin-sensitizing thiazolidinediones.It can reduce insulin resistance by increasing peripheral and liver glucose utilization and insulin sensitivity,mainly in adipose tissue and muscle of PCOS patients,and stimulate glucose transporter(GULT-4) expression and other proteins in the insulin pathway.It also attenuate insulin resistance in the ovary and led to restoration of ovulation and regulation of menstrual.Diane-35 is a complex oral contraceptives.It can play a role of anti-androgen, suppress the excessive secretion of gonadotropin,particularly LH,by stimulating the synthesis of SHBG in liver.Consequently,androgen activity was lower.The progesterone - cyproterone acetate can combine target androgen receptor and suppress androgen activity,so it rapidly improve the clinical manifestations of hyperandrogen.Troglitazone had withdrawn from the market due to hepatotoxicity.At present, no large-scale,long-term studies of use by Pioglitazone in treating patients with PCOS have been reported,so the curative effects and untoward effects of Pioglitazone on patients with PCOS still need to be investigated in lots of clinic trials. Some researches have shown that oral contraceptives(including the Diane-35) can not improve insulin sensitivity,abnormal glucose and lipid metabolism.On the basis of the above background,we attempt to treat PCOS by using insulin sensitizer(pioglitazone,metformin)and Diane-35,in order to explore new therapeutic approaches of PCOS.【Objective】To evaluate the clinical effect of insulin sensitizer(pioglitazone,metformin), combined with Diane-35 in treating patients with PCOS.To measure the level of TNF-αin patients with PCOS,and to explore the relationship with PCOS.【Subject and Method】Selecting 48 women with PCOS as the examination group in our hospital from 3/2007 to 8/2008.8 cases had withdrawed from the trial because economic and other factors.Finally,subjects who had completed trial were divided into two groups according to body mass index(BMI):non-obese group(n=16) and obese group (n=24)..In an another,selecting twenty normal women as control subject.All subjects with PCOS were administrated by pioglitazone,metformin combined with Diane-35,for 6 months;BMI,waist-to-hip-ratio(WHR),the serum LH,FSH,T, E2,PRL,TNFα,TC,TG,LDL-C,HDL-C,LH/FSH,HOM-IR,GAUC,IAUC,fasting,one and two hours blood insulin and glucose concentration on75g load glucose tolerance test(OGTT) were measured and/or calculated before the treatment and after six months therapy.In the same time,the control subjects were measured and/or calculated the same index.Improvent of clinical symptoms such as menstruation,dysgenesia,hirsutism and acne,et al were observed after treatment.Side effects of these drugs were observed every two weeks.Various parametes of insulin resistance,sex hormone,inflammation and lipide metabolisim were compared between PCOS group and normal control group,especially between before and after treatment in PCOS group.【【Result】1.Clinical symptoms of PCOS,comparison among different groups1.1 Clinical symptoms and general situationThere is no difference in age among the two groups.In this study,we observed that the clinical manifestations of patients with PCOS having a high degree of heterogeneity:anovular menstruation or amenorrhea were very common,up to 72.5% (29/40),26 cases of married patients with PCOS have 18 cases(69.2%) were infertile, whether anovular menstruation or amenorrhea,no difference between the obese group and non-obese group.Higher incidence of hirsutism in non-obese PCOS than in obese PCOS.In the patients with PCOS,BMI and WHR were higher than the normal control group(P＜0.01).1.2 Comparison of various parameters between the PCOS group and the control groupFPG,1hPG,2hPG,FINS,1hINS,2hINS,GAUC,IAUC,HOM-IR,T,LH,LH/FSH,TN Fα,LDL-C in the PCOS group were significantly higher than that of the normal control group(P＜0.01),PRLand TG also was higher than the normal control group(P＜0.05),the differences were statistically significant.The difference in E2,FSH,TC, HDL-C between the two groups were no statistically significant(P＞0.05).1.3Comparison in obese group and non-obese groupThis difference was not observed when comparing FPG,TNFα,FSH,LH,E2,T, PRLbetween the obese group and non-obese group.BMI,WHR,1hINS,2hINS, 1hPG,IAUC,GAUCof obese PCOS group were significantly higher than that of the non-obese group(P＜0.01).LH/FSH,2hPG,FINS,HOM-IR are also higher than that of the non-obese group(P＜0.05).2.Improvement of clinical symptoms in PCOS group after treatment and comparison between before and after treatment2.1 The two groups after treatment in patients with clinical symptoms and signs of improvement.Hirsutism and acne were improved to a certain extent.18 cases of infertility patients have 5 cases of successful pregnancy,one and four respectively in the obese group and non-obese group.Pregnancy rate was 16.2%and 36.3%respectively between the obese group and non-obese group.More than half of the patients with PCOS have restore ovulation.The regular menstruation and ovulation ratio was 61.5%and 62.5% respectively between the obese group non-obese group.After treatment,BMI and WHR in obese group than the pre-treatment decreased,the difference were statistically significant;Compared with the pre-treatment,BMI in non-obese group, has increased trends(P＞0.05),WHR was no significant change(P＞0.05).2.2 Changes of insulin level after treatmentTreatment with three drugs resulted in a significant decrease in FINS,1hINS, 2hINS,IAUC,GAUC,HOM-IR in the obese group,the difference has statistical means.Compared with before treatment,1hINS,2hINS,IAUC in the non-obese group a significant decrease after treatment(P＜0.01),GAUC and HOM-IR also have a downward trend(P＞0.05),the difference was not statistically significant.2.3 Changes of sex hormone level after treatmentThe level of LH,T in obese group decreased significantly(P＜0.01),LH/FSH also declined(P＜0.05),the differences is statistically significant;Compared with before treatment,in non-obese group,LH,LH/FSH also significantly decreased,FSH increased(P＜0.01),T decreased(P＜0.05),the difference has statistical significance.2.4 Changes of TNFαafter treatmentTNFαof obese group was significantly decreased(P＜0.01),the difference has statistical significance.2.5 Changes of glucose,lipid after treatmentThe obese group 1hPG,2hPG were significantly decreased(P＜0.01);compared with the pre-treatment,non-obese group 1hPG and 2hPG also declined,but the difference was not statistically significant(P＞0.05).The obese group TG,LDL-C were decreased,HDL-C was increase(P＜0.01), the difference has statistical significance,compared with pre-treatment;After treatment in non-obese group,HDL-C was increased(P＜0.01),TC,TG,HDL-C has no significant changes(P＞0.05).3.Incidence of side effects of PCOS after treatmentIn the early treatment courses,each four cases in obese group and non-obese group had mild gastrointestinal reactions(nausea,vomiting) symptoms,3 cases in non-obese group had dizziness,but can be tolerated,the symptoms were dispeared after a little time.During the treatment.There is no other side effects such as anemia, edema,lactic acidosis etc.happen.Liver and kidney functions were normal after treatment.【Conclusion】1.Hyperandrogen,high LH and LH/FSH,and insulin resistance are the characteristics of most patients with PCOS.Insulin resistance and abnormal glucose metabolism are more serious in obese group than in non-obese group.2.Treatment combination with the insulin sensitizing agent(Pioglitazone,metformin) and(Diane-35) in attenuating insulin resistance and hyperandrogenemia.More importantly,the ovulation and pregnancy rates have been increased.It also reduce the level of inflammatory cytokines TNFα,which indirectly affect PCOS.No seriously adverse events were observed during treatment combination with the insulin sensitizing agent(Pioglitazone,metformin) and(Diane-35).3.Much better decreasing of insulin resistance and improving abnormal glucose metabolism in obese group than non-obese group.So,it may be proved an efficacious therapeutic tool in treating patients with PCOS.4.Patients with PCOS had significantly higher serum TNFαlevel than normal subjects,which suggested that TNFαplay a role in the pathogenesis of PCOS.