Clinical Characteristics And Etiology Heterogeneity Analysis Of Patients With Hypogonadotropin Hypogonadism

Objective: To investigate the clinical features,biochemical profiles,radiolody and causes of the patients with hypogonadotropic hypogonadism(HH).Methods: Medical history,laboratory examination and imaging data were collected in patients with hypogonadotropic hypogonadism clinically diagnosed in the Department of Endocrinology of our hospital from August 2011 to August 2018.Meanwhile,targeted next-generation sequencing was performed in 10 patients.Results: A total of 20 cases of HH patients were included,including 19 males with a chromosome karyotype of 46,XY,and 1 female with a chromosome karyotype of 46,XX.The diagnostic age of the patients was21.3±6.9 years old(11-39 years old),and all patients were taller than the25 th percentile of people of the same age and gender.Male patients showed micropenis,microorchidia,lack of secondary sexual development,some patients present with cryptorchidism.The female patients showed primary amenorrhea,no breast development.Fourteen patients were associated with varying degrees of anosmia,some with other abnormalities(such as cleft lip and palate and skull deformity,etc).The basic values of FSH(0.89±0.79 m IU/ml)and LH(0.53±0.66 m IU/ml)were significantly lower than the normal reference range and T(0.31±0.32ng/ml)were significantly lower than the normal range at the initial diagnosis of 20 patients.The levels of ACTH(21.9±6.9pg/ml),serum cortisol(15.5±5.7Ug/dl)and DHEA-S(177.5±74.5Ug/dl)were normal or slightly low.Thyroid function was in the normal range of all the patients.The GnRH stimulation test showed variable response in different patients.Five patients(25%)had FSH peak at 60 minutes,6 patients(30%)had FSH peak at 90 minutes and five patients(25%)had FSH peak at 120minutes;9 patients(45%)had LH peak at 60 minutes,4 patients(20%)had LH peak at 90 minutes and 2 patients(10%)had LH peak at 120 minutes.Among of them,15 patients showed LH level of 60 minutes lower than 4IU/L,and patient 4 and patient 17 responded well(60min LH ≥8IU/L).Eleven patients were accepted GnRH pumping therapy and 3 patients accepted combination therapy with h CG and h MG.However,the patients showed variable treatment effect with GnRH pulse pump.A total of 11 mutations were found in 6 patients,distributed in 8 genes(CHD7,NOTCH1,JAG1,POLR3 A,FGFR1,NOS1,GNRH1 and SOX10).Four patients were found polygenic mutations.Conclusions:The clinical characteristics of patients with HH mainly manifested as lack of secondary sexual characteristics,decreased sexual desire,infertility,etc.The sex hormone level,GnRH stimulation test and MRI imaging of olfactory bulb and olfactory sulcus are helpful for early diagnosis.GnRH pulse pump or combination therapy with h CG and h MG can promote the development of secondary sexual characteristics,leading to long-term improvement of life quality and fertility.Targeted next-generation sequencing technology is beneficial to early molecular diagnosis.The multiple gene mutations may cause clinical phenotypic heterogeneity,underlying the inconsistent efficacy of GnRH pulse therapy.