Effects Of Recombinant Human Growth Hormone Replacement Therapy On Multiple Pituitary Hormone Deficiency Patients Of Different Ages

BackgroundMultiple pituitary hormone deficiency(MPHD)refers to the impaired production of one or more anterior pituitary hormones in addition to growth hormone(GH).It is a kind of chronic disease accompanied by life and needs dynamic observation.The etiology of MPHD is complex,which can be divided into two categories:congenital and acquired.And there are corresponding imaging findings on MRI.MPHD occur in any age group with different clinical manifestations.Due to lack of pituitary hormones which can raise blood glucose,patients with neonatal onset of MPHD may show hypoglycemia.The main manifestation of children and adolescents with MPHD is growth retardation because children are in the critical period of growth and development.The patients in transitional period may have abnormal blood glucose and blood lipid because of the deficiency of pituitary hormones.Therefore,the clinical manifestations and treatment focused of MPHD patients in different age groups may be different.Because GH can not only promote the body’s linear growth,but also regulate the body’s glucose and lipid metabolism,the purpose of using recombinant human growth hormone(rhGH)replacement therapy in patients with different ages may be different.ObjectivesBy investigating the birth status of patients with MPHD and recording their general characteristics,laboratory examination results and imaging examination results,we aim to analyze and compare the clinical characteristics and pituitary hormone levels of patients with different imaging manifestations,and to explore the incidence of pituitary structural abnormalities in patients with MPHD,and to investigate the different pituitary hormone levels in different types of pituitary structural abnormalitiesThe patients were divided into two parts according to the onset age:neonatal onset,childhood and adolescent onset.The changes of metabolic indexes,especially blood glucose,was followed up after rhGH replacement therapy.For children and adolescents with MPHD,the height improvement after rhGH treatment was followed up.For the patients who were diagnosed with TGHD,the changes of metabolic indexes after rhGH treatment were followed up.Through the analysis of the above follow-up results,we aim to explore the efficacy of rhGH in the treatment of different age groups of patients with MPHD,and then to determine the focus of follow-upSubjects and MethodsSubjects:Case group:A total of 193 patients(142 males and 51 females,aged 9.1±4.3 years)with MPHD diagnosed in pediatric endocrinology clinic and ward of Shandong provincial hospital from September 2012 to June 2020 were selected.According to the age of onset and course of rhGH,the cases meeting the following requirements were selected and analyzed separtely.① 9 patients with MPHD(5 males and 4 females,median age was 60-day)were neonatal onset.② There were 74 cases(58 males and 16 females)with MHPD in childhood and adolescence aged 10.5± 3.2 years.And the course of rhGH treatment was more than 2-year.③ During the study period,32 cases(26 males and 6 females)aged 19.3± 2.8 years were diagnosed with TGHD.Control group:① 23 healthy newborns or infants(12 malea and 11 femals,median age was 62 days)in our hospital at the same time were chosen to be the control group of patients with MPHD onset in neonatal period.There was no significant difference in age and gender between the control group and the case group.②45 healty adolescent and young adults(35 males and 10 femals)aged 18.9±3.5 years were chosen to be the control group of TGHD patients.There was no significant difference in age and gender between the control group and the case groupMethods:1.Comparison of different imaging manifestations of MPHDAccording to the MRI findings in patients with MPHD,all patients under 18 years old were divided into four groups:①PSIS group,② hypophyseal dysplasia group,③ tumor survival group,④normal pituitary structure group.The CA,BA,Ht SDS,BMI SDS and pituitary hormone levels were analyzed and compared among each group2.Research plan for patients with MPHD onset in neonatal periodObjective to evaluate the general characteristics of the MPHD patients with neonatal onset,to analyze the levels of AST,ALT,TC,TG,HDL-C,LDL-C,FBG and GA,and compare with the normal control group.After hormone replacement therapy,they were divided into three groups:oral hormone replacement therapy only for 1 week(non-rhGH treatment group).One week after oral hormone replacement therapy,rhGH was added for 1 month(rhGH-for-1-month group).The patients were treated with rhGH for 4 months(rhGH-group-for-4-month group).The FBG and GA after treatment was compared with that before treatment and control group.3.Research plan for children and adolescents with MPHDMethods:74 patients(58 males and 16 females)with MPHD who had been treated with rhGH for more than 2 years were divided into two groups according to treatment of gonadotropin.Male patients treated with rhGH alone were divided into preadolescent male group(Pre-male group)and female patients were preadolescent female group(Pre-female group).The male patients treated with rhGH and gonadotropin from the beginning of treatment were puberty-male-group 1(Pub-male group 1).The male patients treated with rhGH for at least 2 years at first and then treated with gonadotropin were puberty-male-group 2(Pub-male group 2).The CA,BA,Ht SDS,BMI SDS and GV during the treatment of rhGH before and after puberty were compared.And the general characteristics of patients reached normal adult height was analyzed4.Research plan of TGHD patientsFor the patients with MPHD who met the diagnostic criteria of TGHD,their general conditions were analyzed,and the levels of AST,ALT,TC,TG,HDL-C,LDL-C,FBG,GA and URIC were recorded,and compared with the normal control groupTGHD patients with dyslipidemia were treated with low dose rhGH for 3 months.The changes of AST,ALT,TC,TG,HDL-C,LDL-C,FBG,GA and URIC were evaluated.The relationship between IGF-1 SDS and AST,ALT,TC,TG,HDL-C,LDL-C,FBG,GA,URIC of TGHD patients was analyzed.Results1.Analysis of the results of different imaging findings in patients with MPHDPatients in PSIS group accounted for the largest proportion(98 cases,50.8%).CA/BA of PSIS patients was the largest,and Ht SDS was the smallest(P<0.05).The occurrence of PSIS was correlated with dystocia and asphyxia at birth sepatately(OR 0.345,95%CI 0.121-0.988,P=0.047;OR 0.139,95%CI 0.046-0.425,P≤0.001.TSH level in tumor survival group was significantly lower than that in hypophysis hypoplasia group and normal pituitary structure group(P<0.05).The levels of GH peak,ACTH and FSH in tumor survival group were the lowest(P<0.05).2.The results of follow-up of rhGH treatment in neonatal onset MPHD patientsThere was no difference between case group without tretatemt and contrtol group in AST,ALT,TC,TG,HDL-C,LDL-C(all the P>0.05).FBG and GA were significantly lower than those of control group(P=0.033 and P<0.001,respectively).FBG and GA in the non-rhGH treatment group was higher than those without treatment(P≤0.001 and P=0.049,respcetively),lower than those in the control group(P=0.013 and P ≤0.001,respectively)The levels of FBG and GA in rhGH-for-1-month group were significantly higher than those without treatment and non-rhGH treatment group(all the P<0.05),and FBG was higher than that of control group(P=0.012),and there was no difference on GA between case group and control group(P=0.255)The levels of FBG and GA in rhGH-for-4-month group were significantly higher than those without treatment and non-rhGH treatment group(all the P<0.05).And there was no difference on FBG and GA between rhGH-for-4-month group and control group and rhGH-for-1-month group(all P>0.05).3 The results of follow up of rhGH treatment in children and adolescents with MPHDDruing preadolescent period:there was no difference in GV between Pre-female group and Pre-male group(P>0.05),and GV in the first year was higher than that in the second year(P<0.05).Druing puberty period:the GV of Pub-male group 1 was higher than that of Pub-male group 2 in the first year(P=0.041),but there was no difference in GV in the second year(P=0.947).The GV of Pub-male group 1 in the first year was higher than that in the second year(P=0.046).There was no difference in GV between preadolescent and puberty male patients in the first year of rhGH treatment(P=0.086).Patients with MPHD who reached adult height:the total height benefit during rhGH treatment was positively correlated with GV in the first year(r=0.626,P≤0.001).There was no difference between the ault height and the genetic target height in all patients(P>0.05)4.The results of follow up rhGH treatment in TGHD patientsThere were no difference between TGHD patients without treatment and control group on BMI,SDS,AST,FBG.IGF-1 SDS and HDL-C in TGHD patients without treatment were significantly lower than those in control group(P≤0.001).ALT,TC,TG,LDL-C,GA,URIC were significantly higher than those in control group(P<0.05).IGF-1 SDS in TGHD group treated with rhGH for 3 months was significantly increased(P<0.001),and the levels of TC,TG and URIC were significantly decreased(P<0.05)IGF-1 SDS was negatively correlated with TC,TG,LDL-C and GA,and positively correlated with HDL-C(all P<0.05)Conclusions1.PSIS is the most common hypophyseal dysplasia disease caused MPHD,which can lead to severe growth and development abnormalities.Survivors of intracranial tumors may develop severe MPHD2.Recurrent hypoglycemia is the main manifestation in neonatal onset MPHD.The blood glucose can be improved by the replacement therapy of glucocorticoid and thyroid,but still below normal.And hypoglycemia can be quickly relieved by replacement therapy of rhGH3.Males and females with MPHD had similar effect of promoting growth during rhGH treatment before puberty.The addition of gonadotropin treatment does not have adverse effects on GV.For patents with MPHD who received rhGH treatment,the faster the GV in the first year,the greater the benefit of height in the future.MPHD patients can attain normal adult height following adequate duration of rhGH treatment.4.The metabolic abnormality of TGHD patients was mainly hyperlipidemia,and small dose of rhGH had a positive effect on decreasing blood lipid level of TGHD.