Efficacy Analysis Of Human Chorionic Gonadotropin Or GnRH Pulse Pump In Males With Hypogonadotropic Hypogonadism

BackgroundHypogonadotropic hypogonadism（HH）is a rare disease characterized by insufficient synthesis or secretion of gonadotropin.It is classified as idiopathic hypogonadotropic hypogonadism and pituitary HH due to hypothalamic and pituitary dysfunction.IHH includes Kallmann syndrome（KS）with olfactory disorders and nIHH with normal olfactory.Treatment of the gonadal axis in male HH patients mainly includes testosterone replacement,gonadotropin（hCG alone or combined with HMG/r-FSH）replacement or GnRH pulse replacement.Most patients require long-term or even lifelong treatment.The choice of treatment varies according to their compliance and goals at different stages.Previous studies have suggested that a small number of patients with HH have poor response to gonadotropins.Early treatment with hCG or addition of exogenous testosterone can rapidly induce the secondary sexual characteristics of men with HH without affecting testicular growth and spermatogenesis;hCG alone or combined with exogenous FSH as well as GnRH pump pulse can effectively promote testicular growth and spermatogenesis of men with HH.At present,there is no consensus on the best treatment for inducing secondary sexual development and fertility in males with HH.Randomized controlled clinical studies on different treatment options are still lacking.Object1.To evaluate the efficacy of hCG in males with pituitary HH and IHH;2.To evaluate the efficacy of hCG and GnRH pumps in males with IHH;3.To explore the factors that influence the efficacy in males with HH.MethodProspective follow-up was performed in 69 male patients diagnosed with IHH and 21 male patients diagnosed with pituitary HH at the First Affiliated Hospital of Zhengzhou University.All patients were recorded by endocrinologists for clinical data and underwent a physical examination before treatment.After 3 to 12 months of follow-up,follicle stimulating hormone（FSH）,luteinizing hormone（LH）,testosterone（T）,estrogen（E2）,prolactin（PRL）and liver function were measured.Ultrasound measures the testicular volume and determines the location.Patients with spermatorrhea retained semen analysis,metabolic abnormalities were monitored in patients with metabolic abnormalities.Height,weight,penis length,glans Maximum diameter are measured by fixed endocrinologists.Beard,larynx,morning breech,breast,pubic hair Tanner staging are recorded.Fertility and adverse drug reactions are asked.There are two treatments including Option 1:hCG（2000 IU intramuscularly,3times per week）or random addition of testosterone undecanoate（40 mg orally with milk,twice per day）;Option 2:GnRH pump（initial dose 10 ug/90 min）.21 patients with pituitary HH were defined as group A and treated with Option 1;69 patients with IHH were randomly divided into groups B and C,using Option 1 and 2 respectively;After one year of treatment with hCG,Married patients who are expected to have a child combine with exogenous FSH（r-FSH 75IU subcutaneous injection,twice a week）;Patients with a combination of multiple pituitary hormones are treated with appropriate hormone replacement therapy.The three groups were divided into two subgroups:overweight（BMI≥24kg/m2）and non-overweight（BMI<24kg/m²）according to body mass index,juvenile（age<18 years old）and adult（age≥18 years old）according to the initial age of treatment.large testis（volume≥4 mL）and small testicle（volume<4 mL）according to testicular volume before treatment.Results1.Before treatment,compared with group B,there was no significant difference in the age of treatment,initial age of treatment,body mass index,and penis length of group A;height,bone age,The gap between bone age and actual age were significantly delayed;There is significantly decreased in hemoglobin,red blood cell count,FSH LH,T,growth hormone,thyroid hormone,cortisol and testicular volume,pituitary height;blood lipids,blood uric acid levels increased significantly;Peak of LH,FSH in Gonadotropin releasing hormone stimulation test increased significantly;Peak of T in hCG stimulation test is not significant difference.After 1-5 years of treatment with hCG or addition of testosterone,there was no significant difference in serum T between group A and group B.But within 24 months the testicular volume was significantly behind compared group A with B,After 30 months there was no significant difference between group A and group B;4 cases in group A combine with exogenous FSH and one case（25%）allowed the spouse to naturally conceive,5 cases in group B combined with r-FSH 2-12 months later（40%）gave birth to the spouse naturally;in group B,One case of juvenile KS and three adult nIHH patients confirmed reversal of the gonadal axis.After one year of treatment,there was no significant difference in serum T,testicular increment,and sperm density between patients with hCG and hCG plus testosterone in group A or group B;Compared with non-overweight patients,serum T and T/E₂ were significantly lower in overweight patients;In group B,Compared with small testicles patients,testicles volume is significantly increased in patients with large testes;In patients who were not overweight,adult,or small testes,group B had a significantly increased testicular volume compared to group A.2.Before treatment,Compared with group B,there was no significant difference in the general data of group C.After treatment,there was no significant difference in serum T between group C and group B.The increase in testicular volume in group C was statistically significant at 6 and 12 months;8 of the 13married patients（61.5%）completed fertility,including 3 natural births and 4 births by self-fertilization-embryo transfer（one patient’s spouse had twin pregnancy）.After one year of treatment,in group C,Compared with non-overweight patients,serum T and T/E₂ were significantly lower in overweight patients;Compared with patients with large testicles,The testicular volume was significantly increased in patients;In patients who were overweight,juvenile,or small testes,In patients with overweight,juvenile or small testicles,the testicular volume of group C was significantly increased compared with group B;In patients with small testicles,11/17（64.7%）of group C produced sperm,Compared with group B,the incidence of sperm was higher;in patients with large testicles,there was no significant difference in spermatogenesis,sperm density,and sperm motility between group C and group B.Conclusions1.Treatment of hCG in males with idiopathic HH is superior to males with pituitary HH who are not overweight,or adult,or small testicle.2.Treatment of GnRH pulse is superior to treatment of hCG in males with idiopathic HH who are overweight,not overweight,juvenile or small testicle.