I. What is IHH? IHH is the abbreviation of idiopathic hypogonadotropic hypogonadism, which is a disease characterized by partial or complete absence of pubertal development due to defective synthesis, secretion or action of gonadotropin-releasing hormone (GnRH) or abnormal migration of GnRH neurons resulting in insufficient secretion of pituitary gonadotropins, namely luteinizing hormone (LH) and follicle stimulating hormone (FSH). The disease is a relatively common group of pre-eclampsia. Patients with IHH are classified into nIHH with normal sense of smell and Kallmann syndrome with abnormal sense of smell, depending on whether they have reduced or absent sense of smell. II. What are the clinical features of IHH? The degree of GnRH deficiency in this disease can be complete or partial and correlates with testicular size. The clinical manifestations of patients are mainly sexual dysplasia or hypoplasia, which can be accompanied by olfactory absence or hyposmia, cryptorchidism, cleft palate, harelip, neurogenic deafness, color blindness, gynecomastia, osteoporosis and renal hypoplasia. III. Clinical diagnosis of IHH At present, the clinical diagnosis is mainly based on clinical manifestations, laboratory tests and imaging examinations. See above for clinical manifestations. Laboratory diagnosis is mainly based on low sex hormones and gonadotropins, and some patients may have growth hormone deficiency, normal secretion function of other hormones in the anterior pituitary, and imaging examinations such as pituitary MRI examination shows that hypothalamic-pituitary structure is without occupancy or other abnormalities. In the diagnosis, it is necessary to first exclude tumors in the hypothalamic-pituitary region, pituitary diseases and other systemic metabolic endocrine diseases, exclude systemic malnutrition status affecting hormone secretion, and perform karyotype examination to confirm 46XY karyotype in males and 46XX karyotype in females, and exclude primary diseases of testes and ovaries. IV. Genetic diagnosis of IHH An increasing number of genetic mutations have been found to be associated with IHH. Among them, olfactory defects and GnRH neural migration defects are the etiological basis of the genetics of Kallmann syndrome. There are three main treatment options for IHH: GnRH pulse therapy, human chorionic gonadotropin (hCG) therapy, and androgen supplementation/replacement therapy. 1, GnRH pulse therapy can induce spermatogenesis, using pulse therapy is more in line with the physiological state, only pulsed small amount of GnRH injection in line with the physiological state can restore the pituitary gland’s LH and FSH pulsed secretion. Thus, the development of sexual organs, especially the production of sperm and the conception of the next generation. 2. hCG injection alone can only stimulate the production of testosterone by Ledig cells in the testes and promote secondary sexual characteristics, thus having obvious therapeutic effects but failing to induce spermatogenesis due to the lack of FSH. On the other hand, not all patients respond well to hCG, and those with cryptorchidism and other causes of testicular non-responsiveness or poor response to hCG may not even achieve masculinization. High doses of hCG can block the activity of enzymes related to testosterone synthesis and cause desensitization of the testes. A few patients develop anti-hCG antibodies. Intermittent and continuous injection of hCG often causes male breast enlargement. 3. Androgen replacement therapy is ineffective in inducing and promoting testicular spermatogenesis, and only promotes masculinization. For patients without fertility requirements who only need to maintain their secondary sexual characteristics, simple androgen replacement therapy can be used. In addition to the above 3 methods, the combination of hCG and hMG (urinary gonadotropin in menopausal women) is another option. However, hMG is expensive and the lack of drug supply makes it difficult to promote, at least for the time being, in China. In addition, the biggest disadvantage of this method is that it destroys the physiological characteristics of gonadotropin pulsatile release. In theory, the treatment of hypogonadotropic hypogonadism in men should be preferred to GnRH pulsatile subcutaneous injections, which are certainly effective in long-term regular treatment. In many cases, the use of androgen replacement alone or premature or excessive use of androgen replacement directly leads to impaired testicular development, passive inhibition of androgen production and spermatogenesis in patients, resulting in male infertility. Sixth, GnRH pulsed treatment effect Foreign countries from the 1980s began to use physiological dose and frequency, pulsed administration of GnRH to induce ovulation to treat female infertility and male infertility due to abnormal LHRH secretion. Most data suggest that this therapy results in increased libido, increased frequency and firmness of erections in 100% of patients over 6-10 months, pubic hair and ejaculation in 93%, mature sperm in 73%, and conception rates of more than 90% in their partners.GnRH can initiate pubertal development, maintain masculinization and sexual function, and initiate and maintain spermatogenesis. For most patients, these effects take 3-15 months to reach spermatogenesis, so the course of treatment should not be shorter than six months. Since GnRH treatment can only play a stimulating role in initiating and/or replacing complementary effects, long-term use is prone to side effects such as antibodies, so it can end after reaching sexual development or having children, and can be re-treated if another child is born. VII. Inclusion criteria for pump therapy 1. Patients with hypogonadotropic hypogonadism (IHH), including nIHH with normal olfaction and Kallmann syndrome with abnormal olfaction. 2.Age between 16-45 years old. 3. Not using or discontinuing for more than 3 months preparations of human chorionic gonadotropin HCG, human urinary tocopherol HMG, androgens, estrogens and progestins. The lack of appropriate drug delivery apparatus has long been a bottleneck preventing the widespread implementation of GnRH pulse therapy. The new micropulse pump is characterized by individualized setting of infusion, simple operation and easy portability. Gonarelin has rapid onset and clearance, and the combination of the two is an ideal method for long-term continuous pulse therapy for IHH. VIII. Considerations for the treatment process The most important concern in this study is the increase in testicular volume, gonadotropin and testosterone levels, and the dose of GnRH should be adjusted if needed. 1. The spermatogenic effect was achieved by analysis of semen samples or by sperm investigation of morning urine samples. The ultimate therapeutic goal is to achieve spermatogenesis. In some patients, after sperm production with GnRH treatment, stopping GnRH treatment and continuing with HCG treatment, most are able to maintain sperm production and even continue to improve. If the patient reaches normal testicular volume, but consistently has a lack of sperm or lack of activity, treatment is stopped. The patient is next treated with HCG 1500-3000 IU for intramuscular or subcutaneous injections once to twice a week, and there is still a chance for the patient to produce sperm. 2. Problems that may arise: Pulsatile administration of the drug for a period of time may be followed by insensitivity of the drug. The secretion of gonadotropins can be restored after a short period of discontinuation or by increasing the dose of GnRH. The following factors are related to the treatment effect: the developmental status of puberty before treatment, undeveloped or partially developed or fully developed; the level of inhibin B, high inhibin B is a positive factor; the presence of cryptorchidism, if there is cryptorchidism is a negative factor.