Menopause-related Analysis Of Female Patients After Allogeneic Hematopoietic Stem Cell Transplantation And Development Of A Model To Predict Menstruation After The First Course Of Hormone Replacement Therapy

The incidence of hematologic malignancies(HM)is yearly increasing,with the environment changing and detection methods developing.Meanwhile,chemotherapy,radiotherapy,targeting therapy,hematopoietic stem cell transplantation(HSCT)and other therapeutic modalities are rapidly developing,and thus the lifetime of patients gets increasingly longer.HSCT is sometimes the only treatment to save some HM patients’lives.It is also used in aplastic anemia,Fanconi anemia and other diseases.It includes autologous hematopoietic cell transplant(AHCT)and allogeneic hematopoietic stem cell transplantation(allo-HSCT).Allo-HSCT usually brings severer damages to organs and leads to dysfunction,compared with AHCT.Moreover,patients will receive conditioning before allo-HSCT.Presently,myeloablative conditioning is most commonly used in China,which has lower relapse rates but higher toxic influence.Ovaries are especially sensitive to such toxicity.On the one side,ovaries can secret sex hormones,including estrogen and progestin.Therefore,ovarian dysfunction means apparent decrease of estrogen and induces menstrual abnormalities,or even amenorrhea.It will also lead to menopausal symptoms including:vasomotor symptoms(VMS)such as hot flashes and sweating;genitourinary symptoms which also lead to sexual problems;psychological changes such as depression,irritability and anxiety.Moreover,risks of osteoporosis and dyslipidemia increase as lack of protection from estrogen.Lipids play important roles in bone metabolism.Low lipid levels may cause osteogenic dysfunction,which can in turn decrease bone mineral density(BMD).However,the consumption of lipids in allo-HSCT patients increases because of hematological diseases,high dose of radiotherapy and chemotherapy,and gastrointestinal graft versus host diseases.In addition,the prevailing trend of "being thin and beautiful" nowadays has led to too strict control of lipid intake in young patients,which increases risks of BMD decrease and challenges of long-term health management.Hormone replacement therapy(HRT)has become one of the most important treatments to build artificial menstrual cycles,relieve menopausal symptoms,protect cardiovascular systems and BMD.HRT imitates physiological secretory process by cycle supplement of estrogen and progestin,and shedding of endometrium can induce withdrawal bleeding.It can relieve VMS,psychological,sleeping and sexual problems,which improves the quality of life.It also helps improve BMD,lipid levels and other aspects for long-term benefits.However,estrogen and progesterone also have some side effects,such as possible correlation with endometrial cancer and breast cancer.Therefore,the dosage of estrogen and progesterone are usually carefully considered in clinical practice.In addition,patients may have some misunderstandings about estrogen and progesterone,and they hope to reduce the hormone dose,too.Therefore,the dosage of estrogen is often empirically selected based on individual situation for the first course of HRT,and then adjusted according to menstruation.However,some patients fail to receive ideal menstrual cycle after the first course of HRT,with decreased compliance and follow-up rate.This study presented distributing characteristics on age among menopausal symptoms of female patients after allo-HSCT and the relationship between BMD and lipid levels in premature ovarian insufficiency(POI)patients,which may benefit in providing individual treatment planning.Then we surveyed reasons of the loss of follow-up in POI patients after allo-HSCT who received the first course of HRT in the past decade.It suggested unideal menstruation was one of the main reasons.So,we developed a model to predict menstruation after the first course of HRT.It might both help adjust treatment plans and improve patients’ compliance after providing appropriate psychological consulting.Part Ⅰ Distributing Characteristics on Age among Menopausal Symptoms of Female Patients after Allogeneic Hematopoietic Stem Cell TransplantationObject:To investigate menopausal symptoms of female survivors after allo-HSCT at different ages,which may be helpful for treatment planning.Methods:We followed up female survivors of childbearing age both when transplanted and followed up,who underwent allo-HSCT in the First Affiliated Hospital of Soochow University and the Children’s Hospital of Soochow University from 2012 to 2015.After divided into 4 groups according to follow-up age,Menopause Rating Scales(MRS)were collected to identify the distributing characteristics of menopausal symptoms at different ages.Results:Except for sexual problems(P=0.409),all menopausal symptoms included in MRS were significantly different in 4 groups(all P<0.05).The scores of hot flashes and sweating,heart discomfort,sleep problems and bladder symptoms in the 21-30y group were higher than those in the ≤20y group and the>40y group.The scores of depressive mood,anxiety and physical and mental exhaustion were higher than those in the>40y group.The scores of irritability and joint and muscular discomfort were higher than those in other groups,while the scores of dryness of vagina in the ≤20y group were lower than those in other groups.On the whole,the scores of physical symptoms,psychological symptoms,urogenital system symptoms and total MRS scores appeared different after grouping according to age(all P<0.05).The scores of physical symptoms,psychological symptoms and total MRS scores in the 21-30y group were higher than other groups,the score of psychological symptoms in the>40y group was lower than other groups,and the score of urogenital symptoms in the ≤20y group was lower than other groups.Conclusion:The menopausal symptoms after allo-HSCT showed different distributing characteristics at different ages.Compared with other groups,the menopausal symptoms of patients aged 21-30 may be more obvious,especially physical symptoms and psychological symptoms.The psychological symptoms of patients aged>40,and the urogenital symptoms of patients aged ≤20,are both relatively lighter.This may be related to differences in physiological basis,life pressure,living environment for patients at different ages.Part Ⅱ Relationship between Bone Mineral Density and Lipid Levels of Premature Ovarian Insufficiency Patients after Allogeneic Hematopoietic Stem Cell TransplantationObject:To explore the correlation between BMD and lipid levels in POI patients after allo-HSCT,which may help on the prevention of osteoporosis.Methods:BMD,serum lipid levels,and sex hormones of POI patients after alloHSCT with 20-35 years of age were measured in the First Affiliated Hospital of Soochow University from January 2017 to October 2022.Their basic data,HM and transplantation information were collected.After divided into normal BMD group and decreased BMD group,the Logistic stepwise regression analysis of BMD grouping and serum lipid levels were conducted according to the results of single-factor analysis.Results:In our study,total cholesterol(TC)was measured in the range of 1.686.80mmol/L.Low density lipoprotein cholesterol(LDL-C)was in 1.08-5.34 mmol/L.High density lipoprotein cholesterol(HDL-C)was in 0.80-2.30 mmol/L.Triglyceride(TG)was in 0.31-5.89 mmol/L.Body mass index(BMI)was in 14.13-26.89 kg/m2.In single-factor analysis,there were significant differences of weight,BMI,busulfan equivalent dose(BED),transplantation age,LDL-C,HDL-C,TC and TG,besides lumbar BMD and femoral BMD(all P<0.05).After Logistic stepwise regression analysis and the adjustment of BMI(OR=0.823,95%CI 0.689-0.984)and transplantation age(OR=0.918,95%CI 0.849-0.992),TC was a protective factor for BMD(OR=0.577,95%CI 0.351-0.949),while HDL-C was a risk factor(OR=15.229,95%CI 3.517-65.952).Conclusion:In POI patients after allo-HSCT with 20-35 years old,BMD might be associated with serum lipid levels.In the examination range of this study,the decrease of TC and the increase of HDL-C were associated with the decrease of BMD.Among other non-lipid factors,lower BMI and younger transplantation age suggested higher risks of BMD decrease.It is of significant importance to guide such patients to control lipid levels and improve weight appropriately,which can help improve BMD and reduce risks of osteoporosis.Part Ⅲ Development of a Model to Predict Menstruation after the First Course of Hormone Replacement Therapy in Premature Ovarian Insufficiency Patients after Allogeneic Hematopoietic Stem Cell TransplantationObject:HRT is one of the important treatments for POI patients after allo-HSCT to establish artificial menstrual cycles,relieve low-estrogen symptoms and protect cardiovascular systems and BMD.However,loss of follow-up is hard to decrease in the long-term therapy.We are trying to establish a menstrual prediction model after the first course of HRT to help adjust HRT plans and provide appropriate psychological consulting to increase patients’ compliance with the long-term HRT follow-up.Methods:We surveyed the reasons of the loss of follow-up in POI patients after allo-HSCT who received the first course of HRT in the past decade.Then we recruited POI patients after allo-HSCT who received the first course of HRT in the First Affiliated Hospital of Soochow University from January 2017 to October 2022.Collect their basic data,hematologic and transplantation information,examination and follow-up results.Predictive factors were selected after comparisons according to menstrual outcomes.Patients were randomly divided into training set and test set.The menstrual prediction model was developed based on random forest and verified by the test set.Finally,we made a user interface and deployed to the server.Results:76 patients were missed follow-up in 249 patients who received the first course of HRT.44.74%of them were due to unideal menstruation,which accounted for higher percentage than other reasons.According to the single-factor analysis in 154 patients who recruited for model construction,the predictive factors included outpatient age,transplantation age,BMI,follicle-stimulating hormone(FSH),HRT plans,gravidity and parity.After the initial establishment of the random forest model,we improved it by adjusting ntree to 500,mtry to 6 and training/test set division to 80%/20%.We also used tenfold cross validation to reduce over-fitting.The area under curve(AUC)was 0.768,the sensitivity was 0.695,the specificity was 0.735,and the cutoff calue was 0.763.As verified by the test set,the accuracy of the model prediction was 0.742.A user interface was deployed to the server(https://szdxzn.shinyapps.io/mense).Conclusion:Unideal menstruation might be one of the main reasons of loss of long-term follow-up.This study successfully established a menstrual prediction model for POI patients after allo-HSCT when finished the first course of HRT.The false positive rate was low,suggesting that if the prediction result of the model is unideal menstruation,we may consider adjusting HRT plans and/or guiding patients to adjust BMI.It may also help when providing appropriate psychological consulting to improve patients’ compliance and increase follow-up rate.