Study On The Association And Mechanism Between Low Serum Prolactin And Metabolic Disorder And The Outcomes Of IVF-ET In Infertile Patients With Polycystic Ovary Syndrome

Chapter ?.The association between low serum prolactin and metabolic disorder in infertile patients with PCOSBackground:Prolactin(PRL)has more than 300 other independent functions in addition to regulating the development of breast and lactation.Studies have demonstrated that serum PRL is closely related to metabolism.However,the associations between PRL and metabolic risk are different when serum PRL is within and outside the normal range.It is more likely to have metabolic problems such as insulin resistance,obesity,atherosclerosis and osteoporosis in patients with hyperprolactinemia.When it comes to patients with normal range of PRL level,the relationship between serum PRL and metabolic risk will just be the opposite.Patients with lower PRL level are more likely to have adverse metabolic outcomes such as metabolic syndrome and type 2 diabetes.In other words,too high or too low serum PRL can cause metabolic disorders,but the relationship between low serum PRL within the normal physiological range and metabolic disorder is often easily overlooked.Polycystic ovary syndrome(PCOS)is the most common endocrine and metabolic disorders in women of childbearing age,which is closely associated with insulin resistance,impaired glucose tolerance,hyperlipidemia,hypertension and cardiovascular disease.The pathogenesis of PCOS is still unclear.Since serum PRL plays an important role in regulating metabolism,the correlation between PRL and metabolic disorders in PCOS patients is worth studying and exploring.PCOS patients are often accompanied with hyperprolactinemia,which has attracted sufficient attention in clinical practice.There are also many studies on the metabolic disorder of PCOS caused by hyperprolactinemia.However,the relationship between PRL and metabolism in PCOS patients whose serum PRL are within the normal range has never been concerned.When it is within the normal physiological range,how does the level of serum PRL of PCOS patients compare with the normal population and whether it may be related to the metabolic disorders of PCOS patients are unknown.Also,related studies have not been reported,which deserves further research.In this study,the levels of serum PRL and the association between PRL and metabolic disorder are studied in a large sample of PCOS infertility patients with serum PRL within normal physiological range for the first time,hoping to provide theoretical basis for the future research of PRL metabolic regulation mechanism and the pathogenesis of PCOS.Objective:The aim of this study was to retrospectively analyze the levels of serum PRL and the association with metabolic disorders in infertile patients with PCOS.Methods:A total of 2052 patients with PCOS and 9696 patients with tubal infertility(non-PCOS)undergoing in vitro fertilization and embryo transfer(IVF-ET)at the reproductive medicine center of the first affiliated hospital of Wenzhou Medical University between January 2007 and August 2018 were enrolled in this retrospective study.All patients were treated with IVF-ET for the first time and had the normal range of serum PRL levels.The level of serum PRL,blood pressure,body mass index(BMI),basic endocrine hormones,fasting plasma lipids,fasting plasma glucose(FPG),liver function,thyroid hormone and other parameters of those 11748 patients were measured and analyzed.Furthermore,the waist circumference,hip circumference,fasting serum insulin(FINS),homeostasis model assessment for insulin resistance(HOMA-IR)and HOMA beta cell function index(HOMA-?)of 792 PCOS patients with complete data among the study group were measured and analyzed additionally retrospectively.Result:1.After controlling body mass index(BMI),the levels of serum PRL were significantly lower in 2052 PCOS patients than controls over all age groups(P<0.05).In PCOS patients,serum PRL was significantly and positively correlated with FPG,serum TSH and serum FT4,and significantly and negatively correlated with LH,LH/FSH,TC,TG,LDL-C,AST,ALT,?-GGT,FT3 and FT3/FT4(P<0.05).After adjusted for age and BMI,serum PRL was positively correlated with FPG,TSH and FT4,and negatively correlated with LH and LH/FSH(P<0.05).2.Serum PRL was negatively correlated with waist circumference,hip circumference,FINS,HOMA-IR and HOMA-? in 792 PCOS patients(P<0.05).After adjusted for age and BMI,serum PRL was negatively correlated with FINS,HOMA-IR and HOMA-?(P<0.05).Conclusion:When it is within the normal physiological range,serum PRL levels of PCOS patients are significantly lower than that of the normal population.Low serum PRL may be an important cause of metabolic risk and a good predictor of insulin resistance and ?-cell dysfunction in PCOS patients.Chapter ?.The association between low serum prolactin and the outcomes of in vitro fertilization and embryo transfer in infertile patients with PCOSBackground:Endocrine and metabolic disorders are known to be closely associated with poor maternal history,such as miscarriage and stillbirth.Metabolic disorders of sugar and lipid can not only change the serum biochemical components,but also have a negative impact on the microenvironment of follicular fluid,ultimately reducing the clinical pregnancy rate.Studies have demonstrated that serum PRL plays an important role in metabolism,and both hyperprolactinemia and low serum PRL within the normal physiological range will have adverse effects on metabolism.So is it possible that abnormal serum PRL may also affect pregnancy outcomes through the pathway of metabolism?Or is it possible that this may also be related to the outcomes of in vitro fertilization and embryo transfer(IVF-ET)?So far,these problems are still not clear and have not been reported yet.It is known that hyperprolactinemia may affect the development of follicles and luteal function through the hypothalamic-pituitary-ovarian axis,thus adversely affecting pregnancy outcomes.Patients with hyperprolactinemia had been paid enough attention clinically and were treated effectively.However,the association between patients with low serum PRL within the normal physiological range and pregnancy outcome as well as IVF-ET outcomes could be easily overlooked,which deserves attention and further studies.Our previous clinical study has confirmed that the levels of serum PRL of PCOS patients are lower than that of normal population,and is closely related to metabolic disorders.This study analyzed the possible association between low serum PRL within normal physiological range and the outcomes of IVF-ET in PCOS infertility patients and tubal infertility patients for the first time,hoping to provide theoretical basis for clinical treatment which could effectively improve pregnancy outcomes in the future.Objective:The aim of this retrospective study was to analyze the association between low serum PRL within the normal physiological range and the outcomes of IVF-ET in PCOS infertility patients and tubal infertility patients.Methods:A total of 1414 patients with PCOS and 7430 patients with tubal infertility undergoing IVF-ET at the reproductive medicine center of the first affiliated hospital of Wenzhou Medical University between January 2007 and August 2018 were enrolled in this retrospective study.All patients had the normal range of serum PRL levels and were treated with IVF-ET for the first time and underwent fresh embryos transfer cycles.The association between serum PRL and the outcomes of IVF-ET were analyzed retrospectively.Results:1.1414 PCOS patients were grouped and analyzed according to the median of the levels of serum PRL.The results showed that along with the decrease of PRL,serum LH,total gonadotropin(Gn)dosage and Gn duration increased significantly while serum oestradiol at human chorionic gonadotrop(hCG)injection day decreased significantly(P<0.05).The number of retrieved oocyte,maturation rate of oocytes,clinical pregnancy rate,implantation rate and live birth rate all showed a decreasing tendency and the abortion rate showed an increasing tendency along with the decrease of PRL,but the differences were not statistically significant.After adjusting for age,BMI and other factors,live birth rate was negatively correlated with T and positively correlated with the number of high quality embryos.Patients with 7 to 15 oocytes had the highest live birth rate(P<0.05).There was a negative correlation tendency between PRL and live birth rate,but the difference was no statistically significant.2.7430 patients with tubal infertility were grouped and analyzed according to the median of the levels of serum PRL.The results showed that along with the decrease of PRL,serum T,antral follicle counting(AFC),serum oestradiol at human chorionic gonadotrop(hCG)injection day,the number of retrieved oocyte,mature rate of oocyte,the number of high quality embryos,clinical pregnancy rate,implantation rate and live birth rate decreased significantly,while serum LH,total gonadotropis(Gn)and abortion rate increased significantly(P<0.05).After adjusted for age,body mass index(BMI)and other factors,live birth rate was positively correlated with AFC and the number of high quality embryos,and negatively correlated with age and T(P<0.05).There was a negative correlation tendency between PRL and live birth rate of patients with tubal infertility,but the difference was no statistically significant.Serum PRL was not an independent factor in the live birth rate of patients with tubal infertility.Conclusion:Low serum PRL within the normal physiological range affects the results of superovulation and laboratory of PCOS infertility patients and tubal infertility patients,and shows a negative correlation tendency with live birth rate.However,there is insufficient evidence to show that low serum PRL is an independent factor in the live birth rate,which needs further studies to confirm the association between low serum PRL and the outcomes of IVF-ET..Chapter ?.The effect and mechanism research of prolactin and its receptor-mediated JAK2/STAT5 signaling pathway on lipid metabolismBackground:The combination of prolactin and the receptor activates the corresponding intracellular signaling transduction pathway,thus acting on the target genes and implementing biological functions.Studies have shown that PRL is closely related to metabolism.However,due to the diversity of PRL receptors and the different regulatory mechanisms of different types of receptors,the signaling pathway and regulation mode after it binds to the receptor are extremely complicated.The specific way through which PRL and its receptors regulates metabolism is still unclear.JAK/STAT pathway is the first signaling transduction pathway identified in PRL.It is also the common pathway of signaling transduction of many other cytokines and growth factors,and is widely involved in important biological processes such as cell proliferation,differentiation,apoptosis and energy metabolism.Since the metabolic regulation of PRL is still unclear and JAK2/STAT5 pathway is closely related to metabolism,the regulation effect of PRL and its receptor-mediated JAK2/STAT5 pathway on metabolism has become the focus of our attention.Studies have found that PRL can activate the JAK2/STAT5 pathway,thus regulating the synthesis and secretion of lactose,milk fat and milk protein in mammary epithelial cells.However,relevant studies were sporadic and mainly focus on breast development and breast cancer research.In addition,the research on the transcription of related genes by PRL has always been focused on mammary epithelial cells and little attention has been paid to the research of lipocytes.Since adipose tissue plays an important role in secretion and metabolism in the body,it is more meaningful to choose lipocytes as carriers in the metabolic mechanism research of PRL and its receptor regulated JAK2/STAT5 pathway.In addition,there is a kind of agent-effect relationship in the PRL/PRLR-mediated JAK2/STAT5 signaling pathway and the concentrations of PRL required to produce normal effects in different species,tissues and cells vary.However,it is not clear what species,what tissues and what cells need PRL concentrations to produce normal effect.Abnormal activation of JAK2/STAT5 signaling pathway may play a key regulatory role in the onset of certain diseases,like tumors and leukemia.Too high or too low serum PRL can cause metabolic disorder of PCOS patients,and whether they might play a role in the occurrence of PCOS through abnormal activation of JAK2/STAT5 pathway is unknown,which deserves further study.However,the regulation mechanism of PRL and the pathogenesis of PCOS are too complex,and many researches are still in the initial stage.Our study aimed to establish an IR cell model and observe changes of the JAK2/STAT5 signaling pathway in IR cells treated by different concentration of PRL or PRLR overexpression for the first time,so as to briefly discuss the relationship and related mechanism between RPL and lipid metabolism,which could ultimately provide theoretical basis for the future exploration of the metabolic regulation mechanism of PRL and the pathogenesis of PCOS as well as the effective clinical treatment scheme of metabolism-related disease.Objective:To explore the effect and mechanism of prolactin and its receptor-mediated JAK2/STAT5 signaling pathway on lipid metabolism.Methods:SW872 preadipocytes were induced to mature adipocytes through oleic acid differentiation.Oil red O was used for identification and model IR was established through oleic acid incubation.High,medium and low concentration of PRL were used for intervention in IR model cells.The expression of PRLR,JAK2,p-JAK2,STAT5 and p-STAT5 protein were detected by Western blot 24 hours and 48 hours after the intervention.TG content in the cells was detected by TG detection reagent.PRLR overexpression vector was constructed,and the vector and empty vector were transfected into mature fat cells.Western blot were used to verify transfection efficiency and transfect IR model cells.The expression of PRLR,JAK2,p-JAK2,STAT5 and p-STAT5 protein were detected by Western blot,and TG content in the cells was detected.Results:The results of oil red O staining showed that the lipid content in the high and medium concentration of PRL intervention group was significantly higher than that in the IR model group(P<0.05).Compared with the model group,TG content in the cells increased significantly 24h and 48h after PRL intervention,and with the increase of PRL concentration,TG content also increased(P<0.05).The results of Western blot showed that,compared with the control group,the expression of PRLR,p-JAK2 and p-STAT5 were significantly decreased 24h and 48h after PRL intervention(P<0.05).Compared with the model group,the expression of PRLR,p-JAK2 and p-STAT5 increased significantly in the high-concentration group(P<0.05).Overexpression of PRLR significantly increased the TG content in the IR model(P<0.05).The results of Western blot showed that compared with the control group,the expression of PRLR,JAK2,p-JAK2 STAT5 and p-STAT5 in the IR model group were significantly decreased.When compared with the model group,the expression of PRLR,JAK2,p-JAK2 STAT5 and p-STAT5 in the PRLR overexpression group were significantly increased(P<0.05).Conclusion:PRL and its receptors are related to lipid metabolism.The JAK2/STAT5 signaling pathway plays an important role in lipid metabolism.PRL intervention and PRLR overexpression can increase TG deposition in adipocytes through abnormal activation of JAK2/STAT5 pathway and affect lipid metabolism.However,the concentration required for PRL to produce normal effect in adipocytes and the correlation between PCOS and abnormal activation of PRL and its receptor-mediated AK2/STAT5 pathway need to be further investigated.