| BackgroundDiminished ovarian reserve(DOR)may lead to impaired fertility in women.Therefore,DOR is one of the indications of assisted reproductive technology(ART)therapy.The main method of ART is in vitro fertilization/intracytoplasmic sperm injection-embryo transfer(IVF/ICSI-ET),and controlled ovarian stimulation(COS)is the most commonly used clinical protocol for IVF/ICSI-ET to achieve good clinical outcomes.In the process of COS,the pathological state of ovarian poor response to stimulation is called poor ovarian response(POR),and DOR is the most important cause of POR.Researches shows that DOR,POR may develop into ovarian insufficiency or failure.With the deepening understanding of ovarian insufficiency and ovarian failure,the concept of premature ovarian insufficiency(POI)was formally updated and the diagnostic criteria of POI was put forward,including menstrual abnormalities and biochemical abnormalities,abnormal menstrual/amenorrhea at least 4 months,and an elevated FSH level>25 IU/L on two occasions>4 weeks apart.However,the criteria is still controversial because it is only an expert consensus,lack of support from clinical research data.With regard to diagnosis,treatment and health management of POI,in addition to severely impaired reproductive function in POI patients,their risk of anxiety,depression,osteoporosis,dyslipidemia,and cardiovascular disease may also increase significantly.In addition,the process of development and fluctuation of POI at each stage is still to be explored.The etiology of POI are complex and diverse:genetic(chromosomal and genetic defects),autoimmune,and iatrogenic factors could lead to POI.In addition,environmental factors,infectious factors,lifestyle may all contribute to the occurrence of POI.However,there is still about 65%of the POI patients with unclear etiology.Therefore,the etiology and risk factors of POI remain to be further explored.To date,there are few reports on the clinical features of POR cycles in patients with DOR after COS.Then,what are the clinical features of IVF/ICSI-ET in patients with DOR and POR?What are the factors affecting their pregnancy outcomes?At present,there are few reports on whether DOR or POR will develop into POI.In addition,if DOR and POR will develop into POI,what are the characteristics and risk factors?Therefore,this topic will explore three issues above and provide a further guidance for clinical diagnosis,treatment and health management of POI.Part Ⅰ Analysis of characteristics and clinical outcomes of women with DOR and POR during IVF/ICSI-ETObjectiveThe clinical data of patients with DOR and POR during IVF/ICSI-ET were analyzed to provide a guidance for clinical treatment.MethodsA retrospective study of DOR and POR patients who underwent IVF/ICSI-ET at our center from November 2011 to May 2017 was performed.The clinical data were analyzed horizontally and vertically.141 patients who conduct IVF/ICSI-ET in our reproductive center that fulfilled the following criteria(both of①② and one of ③④⑤⑥)were retrospectively enrolled:①infertile female whose age were below 40 years at the time of treatment;②at least 1 cycle,the number of retrievaled oocytes is less than 3;③the number of basal AFC is less than 3;④the level of FSH is higher than 10 IU/L;⑤FSH/LH>2;⑥AMH<0.5～1.1ng/ml.Exclusion criteria:①patients who were diagnosed as Polycystic ovary(PCO)or Polycystic ovary syndrome;②amenorrhea result from hyperprolactinemia,uterine factors and other non-ovarian factors;③hypogonadotropic amenorrhea.Horizontal analysis:according to the previous highest basal FSH level,patients were divided into 3 groups:group A(FSH ≤ 15 IU/L),group B(15<FSH ≤ 25 IU/L),group C(FSH>25 IU/L).Analyze the data of patients who perform IVF/ICSI-ET cycle.Vertical analysis:Analyze the clinical outcomes at different nodes of DOR patients after COS.Comparing the differences in the clinical parameters associated with non-available embryo group and available embryo group,non-clinical pregnancy group and clinical pregnancy group,respectively.And then select the variables that were statistically significant in the univariate analysis as independent variables,available embryos or pregnancy as the corresponding dependent variable respectively,and analyze with multivariate non-conditional logistic regression.Besides,through classification tree analysis,estimate the value of AFC on the number of high-quality embryos and the average AFC on the number of accumulated high-quality embryos.SPSS(version 20.0)was used for analysis.P<0.05 was considered statistically significant.There were differences in clinical parameters between non-available embryo group and available embryo group,between the non-clinical pregnancy group,and clinical pregnancy group,Results1 The results of the horizontal analysis of the different levels of the highest basal FSH are listed as follow:there were significant differences in patient among all of the parameters except for age and Body mass index(BMI).In infertility duration,mean AFC,and initiation cycle AFC,group C<group B<Group A:In the level of the highest basal FSH,initiation cycle FSH and their corresponding LH,group A<group B<C group;at E2(when the highest basal FSH),initiation cycle E2,group B<group C<A group.Clinical characteristics of the patients’ cycle:there were significant differences in patient among all of the parameters except for maturation rate,fertilization rate,and available embryo rate.In term of the cancellation rate of embryo transfer in fresh cycle,Group A<Group C<Group B;In term of the cancellation rate of cycle before oocytes retrieval,the rate of the cycle without obtaining oocytes,the rate of the cycle without available embryo,group A<group B<C group;The number of oocytes retrieved per cycle,group C<Group B<group A;in the selection of cycle protocal,thereinto,the proportion of routine protocal and micro stimulation protocol in group A was the highest,accounting for 80.1%and 11.8%respectively.The proportion of routine protocal and micro stimulation protocol in group B was the highest,accounting for 61.5%and 20.5%respectively,while the proportion of routine protocal and natural cycle protocal in group C was the highest,both of which account for 39.6%.Clinical outcome of patients:In the number of embryo transfer per cycle in the fresh cycle,group C<group B<group A,the overall differences were statistically significant;comparing the rate of clinical pregnancy and early abortion in the fresh cycle,the overall differences were not statistically significant.Comparison of cumulative number of transplants per patient,cumulative pregnancy rate per patient,embryo implantation rate per patient,live birth rate per patient,there was no significant difference among 3 groups.while there was a significant difference in the cumulative number of embryo transfer per patient:group C<group A = group B.Comparison of clinical pregnancy rate,embryo implantation rate and live birth rate of all embryo transfer cycles,there was no significant difference among 3 groups either.2 In the univariate analysis of non-available embryos group and available embryos group,basal AFC in the start-up cycle,level of basal FSH in the start-up cycle and the previous highest level of basal FSH and their respective corresponding LH,COS protocol selection,Gn days,total Gn dose,number of follicles ≥ 14mm on the trigger day and number of follicles on the trigger day ≥ 10mm were statistically significant.Further multivariate logistic regression analysis showed that the number of follicles ≥ 14mm on the trigger day was positively correlated with the odds of having available embryos(P<0.001,OR=1.75),3 In the univariate analysis of non-pregnancy group and the pregnancy group,endometrial thickness on trigger day,number of embryo transfer,and number of high-quality embryo transfer were statistically significant.Further multivariate logistic regression analysis showed that endometrial thickness on triggerday(P=0.008,OR=1.32),and number of high-quality embryos transfer(P=0.004,OR=2.50)was positively correlated with the odds of pregnancy.4 The start-up cycle AFC predicted the number of high-quality embryos:the average number of high-quality embryos in the start-up cycle was 0.535 in AFC≤6 group;and the average number of high-quality embryos in the start-up cycle was 0.990 in AFC>6 group.The patient’s odds of no accumulating high-quality embryos is 48.8%in AFC≤6 group;the patient’s odds of no accumulating high-quality embryos is 21.8%in AFC>6 group.Conclusion1 The higher the previous highest basal FSH was,the worse the ovarian reserve function was.In addition,even if the ovarian reserve function is seriously degraded,even reaching POI,there is still a chance of getting a normal pregnancy.2 The number of follicles ≥ 14mm on trigger day was related to the odds of having available embryos.3 The endometrial thickness on trigger day,the number of high-quality embryo transfer were the most important factors affecting the pregnancy cycle of embryo transfer in fresh cycles.4 Basal AFC had a certain predictive value for predicting the number of high-quality embryos.Part Ⅱ Follow-up of ovarian reserve function and physical and psychological health of women with DOR after IVF/ICSI-ET treatmentObjectiveTo study the feature of ovarian reserve function,physical and psychological status of patients with DOR after IVF/ICSI-ET treatment,and study whether patients with DOR would develop into POI and its characteristics preliminarily.MethodsThe study participants were outpatient infertility women with DOR and POI of childbearing age from November 2013 to October 2017,besides those in Part I.Inclusion and exclusion criteria were the same as those of Part I.In addition,patients who had undergone hematopoietic stem cell transplantation and whose age were more than 40 years old during the follow-up period before diagnosed with POI were excluded.With the consent of the patients,collecting and following-up patient general information and clinical data related to ovarian reserve function.Record the pelvic ultrasound,AMH and sex hormone test results,other systemic examination results,including bone density,blood lipids,and other health conditions.the modified Kupperman perimenopausal symptoms assessment,self-evaluation of anxiety scale questionnaire(SAS)and self-evaluation of depression scale questionnaire(SDS)were filled in by POI patients voluntarily.SPSS(version 20.0)was used for analysis.Results1 Among the 92 patients who had previously been diagnosed with DOR,20 were unwilling to cooperate with the follow-up examinations;60(83.33%)were still in the DOR state;5(6.94%)were in the POI state;and 7(9.72%)were in suspicious POI status.Patients who were previously DOR patients but develpeded to POI during follow-up period accounted for 16.67%.2 Among the 38 patients who had previously fulfilled the diagnostic criteria of POI,12 were unable to follow the follow-up examination;24(92.31%)were still in POI status and 2(7.69%)were in DOR status.3 Follow-up of ovarian function in patients with DOR and POI:patients were divided into non-POI group and POI group.The age during previous treatment of the two groups was 32.5±3.8 years and 32.4±5.2 years respectively;The age during follow-up period was 35.2±3.6 years and 33.2±5.4 years,respectively.4 There were significant differences in AMH,basal E2 between the two groups(POI group<non-POI group).Besides,there were significant differences in basal FSH,basal LH,difference value of FSH,basal AFC,diameter of the ovary can be displayed,average diameter of the uterus,odds of invisible ovary between the two groups(POI group>non-POI group).5 In the non-POI group,the basal FSH was lower than the previous highest basal FSH,the difference was statistically significant,while there was no significant difference when comparing follow-up period with the previous period in other ovarian function-related clinical parameters.In the POI group,there was no significant difference when comparing follow-up period with the previous period in all of ovarian function-related clinical parameters.The difference between two groups was significant.6 106 patients had completed the modified Kupperman perimenopausal symptoms.27 patients(44.3%)had perimenopausal symptoms in non-POI group(n=61),whose average score of perimenopausal symptoms was 6.11±3.77,29 patients(64.4%)had moderately severe symptoms in POI group(n=45),whose average score of perimenopausal symptoms was 8.78±5.92.The difference was significant between two groups.7 98 patients had completed self-evaluation of anxiety scale questionnaire(SAS)and self-evaluation of depression scale questionnaire(SDS).2 patients(3.4%)showed anxiety symptoms in the non-POI group(n=58),while 9 patients(22.5%)showed anxiety symptoms in the POI group(n=40).58patients(31.0%)showed depression symptoms in the non-POI group(n=58),while21 patients(52.5%)showed anxiety symptoms in the POI group(n=40).The difference were significant in both anxiety scale and depression scale between two groups.8 Bone mineral density:there were 16 POI patients who performed the bone mineral density examination,9(56.25%)showed normal bone mineral density,5(31.25%)showed low bone mass change,and 2(12.50%)showed osteoporosis.9 Lipid metabolism:there were 17 patients who performed the bone mineral density examination in non-POI group,and 13(76.5%)of them had abnormal lipid metabolism,while there were 18 patients who performed the bone mineral density examination in POI group,and 8(44.4%)of them had abnormal lipid metabolism,yet no significant difference were observed.10 Other health conditions:Of the POI patients,2(7.69%)patients previously had not got pregnant with IVF/ICSI-ET treatment performed in our center,but they later were pregnant naturally and each delivered 1 healthy live-born infant successfully;there was 1 patient with congenital absence of right ovary,single angle uterus,right kidney absent;there is a patient with frequent fractures,urinary tract infections;1 patient was diagnosed as breast cancer during follow-up period;1 patient during follow-up period,there was a sensory abnormality in her extremities,manifest as numbness of fingers and toes.Conclusion1 POI was a progressive and fluctuating development process:ovarian reserve function of some patients with DOR would gradually decline,developing into POI during follow-up,accounting for 16.67%,ranging from 4 months to 4 years;ovarian reserve function of some patients with POI would take a turn for the better transitorily,accounting for 7.69%.2 The level of FSH fluctuated in a large range.To date,FSH is the only biochemical parameters of the diagnosis of POI,which is not conducive to the early diagnosis and treatment of POI.Therefore,more accurate and appropriate diagnostic criteria of POI combined clinical parameters such as AFC or AMH are still supposed to be explored.2 The fluctuation range of FSH was relatively large and unstable.At present,the biochemical indicators for the diagnosis of POI are only FSH,which is not conducive to the discovery of early POI and timely treatment.Therefore,more accurate and appropriate diagnostic criteria for POI combined with AFC or AMH are for further study.3 POI seriously jeopardizes women’s reproductive health,physical health and psychological health,and even at the stage of DOR,it has begun to jeopardize their health.In the absence of contraindications,insisting on HRT can alleviate the symptoms associated with estrogen deficiency in patients with POI.At the same time,it has protective effects on multiple systems of body,including the skeletal system,cardiovascular system,urinary system,and nervous system.Part Ⅲ Analysis of risk factors on developing into POI in women with DORObjectiveTo study etiology and risk factors o on developing into POI in women with DOR by analyze the clinical data of patients with DOR or POR and patients with POI during follow-up period.MethodsThe study participants were the same with Part Ⅱ.Reading the literature,formulating the "Female Reproductive Health Survey",and collecting the data of history and follow-up period.The investigation included:general conditions,menstruation and pregnancy history,lifestyle and behavioral habits,past history,family history,and chromosome karyotype.Perimenopausal symptoms and psychological symptoms.Then analyze all data using of chi-square test,Fisher’s exact test,t test and find out how these factors influence POI occurrence.And then select POI as the dependent variable,P<0.1 factors as independent variables,and analyze with multivariate non-conditional logistic regression.P<0.05 was considered statistically significant.Results1 Factors that were statistically different between the non-POI group and the POI group are listed as follows:The POI group was larger than the non-POI group at the proportion of menarche age≤12 years,abnormal odds of menstrual cycle(85%VS 28.9%),and hypomenorrhea(44.4%VS 13.4%).In terms of the number of pregnancies,the proportions of 0,1 and 2 times of pregnancy in non-POI patients were 27.8%,38.9%,and 33.3%,respectively,while those in the POI group were 53.2%,12.8%,and 34.0%,respectively;in the history of labor,odds of no history of childbirth in the non-POI group is 44.4%,and 66.0%in the POI group.In terms of frequency of vegetable intake,the proportion of<3 times per week,3-6 times per week,and ≥7 times per week was 2.2%,13.3%,and 84.4%respectively in the non-POI group while those in the POI group was 17.8%and 35.3%,52,9%respectively.In terms of frequency of fruit intake,the proportion of<3 times per week,3-6 times per week,and ≥7 times per week was 17.8%,35.6%,46.7%respectively in the non-POI group while those in the POI group was 38.2%,41.2%,20.6%respectively.In terms of regular deliberate diet(23.5%VS 4.4%),passive smoking(55.0%VS 30.4%),contact history of other toxic and hazardous substances in work(23.5%VS 4.4%),regular work shifts(32.4%VS 13.3%),proportion of sleep time less than 7 hours per night(55.9%VS 20.0%),POI group were greater than non-POI group.In terms of odds of history of salpingitis(28.2%VS 37.8%),POI group was smaller than that of non-POI group;in terms of symptoms of anxiety(22.5%VS3.4%),depression(52.5%VS 31.0%),odds of having female relatives with amenorrhea before 40 years of age(12.5%VS 0),POI group is larger than non-POI group.2 Multivariate non-conditional logistic regression analysis:select occurrence of POI as the dependent variable,menarche age,menstrual cycle,menstrual amount,taking oral contraceptive,gravidity,delivery times,frequency of vegetable intake,frequency of fruit intake,frequency of bean products intake,dieting,passive smoking,contact history of other toxic and hazardous substances in work,sleeping time,regular work shifts,salpingitis,connective tissue disease,autoimmune disease or disorder,having female relatives with amenorrhea before 40 years of age,perimenopause syndrome,anxiety symptom,depressive symptoms as 21 independent variables in total,and analyze with multivariate non-conditional logistic regression.Four factors,including menstrual cycle,gravidity,dieting,autoimmune disease or disorder were selected into the final regression equation.The regression coefficients were 2.18,-4.28,1.71,3.61 respectively and OR were 8.86,0.014,5.54,36.99 respectively.Conclusion1 menstrual cycle,gravidity,regular dieting,autoimmune disease or disorder were the most important factors affecting DOR patients developing into POI.2 Abnormal menstrual cycle was a risk factor affecting DOR patients developing into POI.3 That number of pregnancies was one time is a protective factor affecting DOR patients developing into POI,while the number of pregnancy is more than 2 times is not related to POI.4 Regular dieting was a risk factor affecting DOR patients developing into POI.5 Autoimmune disease or disorder was a risk factor affecting DOR patients developing into POI. |
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