I. Gonadotropin-releasing hormone GnRH pulse pump (pituitary pump) treatment definition GnRH pulse pump (pituitary pump) treatment is the use of artificial intelligence-controlled miniature GnRH input device, through the pulse subcutaneous injection of GnRH analogues, simulating the hypothalamus GnRH physiological pulse secretion pattern, so as to achieve effective stimulation of pituitary gland secretion gonadotropin, and then promote gonadal development, secretion of This is a method to effectively stimulate the pituitary gland to secrete gonadotropins, thereby promoting gonadal development, secretion of sex hormones and gametogenesis, and fertility. (1) The working principle of GnRH pulse therapy: Puberty is a necessary stage in the transition from childhood to adulthood, and is the process by which biological individuals move towards sexual maturity and reproductive capacity. The initiation of puberty in the physiological state is marked by the pulsatile release of GnRH during sleep in the hypothalamus, gradually forming regular GnRH pulse peaks with a frequency of about 60-90 minutes/time, and the secretion of GnRH pulses stimulates the pituitary gland to secrete luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which in turn induces the gonads to secrete sex hormones and gametogenesis, constituting a feedback and negative feedback system for the hypothalamic-pituitary-gonadal axis The hypothalamic-pituitary-gonadal axis feedback and negative feedback system. If GnRH pulses are secreted abnormally, delayed puberty, low sex hormones, and even infertility occur. Among the congenital disorders, idiopathic hypogonadotropic hypogonadism (IHH) is the most common. Among the acquired factors, secondary central amenorrhea is more common in women. GnRH pulse therapy is accomplished by the GnRH pulse pump, an artificially controlled adjustable miniature pulse pump, which simulates the secretion of hypothalamic GnRH pulses through subcutaneous infusion of GnRH drugs to achieve the process of puberty, promote gonadal development, and ultimately gain fertility, and is the most consistent with the hypothalamic-pituitary gland It is the treatment method that is most consistent with the physiological regulation mechanism of hypothalamic-pituitary axis. The GnRH pulse pump consists of four parts: an artificial intelligence control system containing a microelectronic chip, a battery-operated mechanical pump system, a drug reservoir, and a subcutaneous infusion device connected to it. The front end of the infusion tube can be buried under the patient’s skin. In working condition, the pump mechanical system receives the command from the control system, drives the piston in the drug reservoir, and feeds the GnRH analogue through the infusion tube subcutaneously according to the predetermined setting. (2) Development history and application status of GnRH pulse therapy The clinical application of GnRH pulse therapy began in 1982, mainly for the treatment of IHH. In the same period, domestic GnRH pulse pump was developed and tried in the clinic. At the beginning of the 21st century, the new pulse pump with micro motor technology and specially developed artificial intelligence control system was significantly reduced in size and could be infused at regular intervals and doses; the frequency and dose were adjustable; the pulse infusion was rapid and precise; the operation was convenient and safe. At present, the only foreign registered market is CRONOFE micro pulse infusion pump. Zyklomat micro pulse infusion pump, which has the function of adjusting pulse time and dose, is still in the clinical research stage. Clinical evidence of GnRH pulse therapy According to domestic and foreign literature, the 2-year spermatogenesis rate of traditional human chorionic gonadotropin (hCG) combined with human urogenital gonadotropin (hMG) for male IHH patients is about 30%-50%, but patient compliance is poor and secondary failure may occur with long-term use; for female IHH patients, the effect of promoting the development of secondary sex characteristics is poor. gnRH pulse therapy is more in line with GnRH pulse therapy is more in line with the physiological pattern and significantly better than traditional treatment in terms of attainment rate and efficacy. (1) Reconstruction of hypothalamic-pituitary-gonadal axis, effectively simulating puberty initiation; (2) Significant increase of testicular volume in males, which can make cryptorchid descend to scrotum; (3) Significant increase of ovarian volume and follicle development in females. 2. Changes in gonadal function (1) higher sperm production rate and quality; (2) regular ovulatory menstrual cycle; (3) higher conception rate; (4) effective supplementation of artificially assisted reproduction (ART) technology; 3. Changes in secondary sexual characteristics (1) manifested by beard hair growth, prominent throat nodes, thick bones, and low voice; (2) female breast development, delicate skin, rich subcutaneous fat, pelvis wide, and a sharp voice. 4. Quality of life (physical fitness, bone density, satisfaction, etc.) (1) Reduce the risk of ovulation promotion; (2) Reduce adverse reactions; (3) Improve compliance; (4) Improve patients’ physical fitness, bone density, and satisfaction with sexual life. 4.Objectives, indications and contraindications of GnRH pulse therapy 1.Objectives of GnRH pulse therapy Simulating the physiological GnRH pulse secretion pattern of hypothalamus, GnRH analogues are artificially given by continuous infusion according to a certain pulse rhythm to achieve the purpose of reestablishing the endocrine function of hypothalamic-pituitary-gonadal axis. 2.Goals of GnRH pulse therapy Short-term goals (≤6 months): (1) restoration of ovulatory menstrual cycle and conception in females; (2) confirmation of somatic delayed puberty (CDP) and induction of puberty initiation in adolescents. Long-term goals (>6 months): (1) Promote and maintain the development of secondary sexual characteristics (2) Restore fertility (3) Improve bone density and prevent osteoporosis 3. Indications As a device for continuous subcutaneous infusion of GnRH, GnRH pulse therapy is in principle indicated for all patients with abnormal secretion of GnRH pulses and with intact pituitary-gonadal reserve function and fertility intention. Males (1) Patients with clinically confirmed IHH; (2) Diagnosis and treatment of CDP. Female (1) Patients with clinically confirmed IHH (2) Diagnosis and treatment of CDP (3) Idiopathic central secondary amenorrhea, adjustment of menstrual cycle and pregnancy promotion; (4) Non-obese PCOS adjustment of menstrual cycle and pregnancy promotion. 4, contraindications (1) primary gonadal insufficiency; (2) hypopituitarism; (3) patients allergic to GnRH pulse pump drugs or infusion tube; (4) combined with other diseases, clinical specialists determine that treatment is not appropriate. V. GnRH pulse treatment methods 1. GnRH pulse treatment using GnRH drugs Gonarelin (molecular formula C55H75N17O13) is a chemically synthesized decapeptide GnRH, intravenous injection of 2 minutes, the blood concentration will reach its peak, the half-life of 20 minutes, very suitable for simulating GnRH pulse. Other types of long-acting GnRH analogues are usually used to interfere with normal GnRH secretion in the hypothalamus, so they are not recommended for pulse therapy use. 2.Initial setup of GnRH pulse therapy (1) Gonarelin solution configuration and installation Gonarelin for injection, pumped into reservoir and placed in GnRH pulse pump at a concentration of 200μg/ml (600μg for 6 drugs at a time), connected to infusion tube and subcutaneous infusion device. (2) Initial dose and frequency setting Set the pulse pump for 1 pulse every 90 minutes, 10μg subcutaneous infusion each time, for a total of 16 pulses in 24 hours. (3) Trial wear period (3-5 days): Adverse reaction observation: allergy, degree of activity limitation, patient acceptance; efficacy assessment: if serum LH and/or FSH is ≥1mIU/ml after treatment, it indicates that GnRH pulse is effective. Patients should be popularized and trained on the knowledge and operation related to pulse therapy during the period. 3.Dose adjustment of GnRH pulse infusion: The principle of dose adjustment is based on self sexual experience (penile morning erection, erection frequency; masturbation, seminal emission frequency, libido, sexual life quality, quality of life score), physical examination (pubic hair distribution, testes, external genital development, breast development Tanner score), sex hormone examination (FSH, LH, E2, T, P, PRL) and gonadal ultrasound The results should be dynamically adjusted and should be followed up every 1 to 3 months. For male patients treated for more than 6 months, reference should also be made to routine semen examination. Must be under the guidance of professional physicians for dose adjustment, not easily changed. 4, GnRH pulse input frequency adjustment: general GnRH pulse frequency fixed at 90 minutes, for all male patients and more than 80% of female patients can have the ideal treatment effect, do not need to adjust. However, for a small number of female IHH patients, fixed frequency GnRH pulses can only promote follicle formation (LH, FSH, E2 in the normal range of follicular phase, ultrasound suggestive of ovarian polycystic structure and endometrium <8mm) and cannot induce ovulation and menstrual flow. For such patients, if there is still no ovulatory menstrual cycle after 6 months of fixed frequency treatment, frequency GnRH pulse therapy can be considered. 5.Drug elution period before GnRH pulse therapy (1)Before GnRH pulse therapy, HCG, HMG, androgen or estrogen-progestin replacement therapy should be stopped for at least 1 month. (2)During GnRH pulse therapy, try to avoid the use of sex hormone-related drugs that interfere with the hypothalamic-pituitary-gonadal axis. 6. Termination of treatment (1) According to the physiological mechanism and clinical use experience, female patients are recommended to terminate GnRH pulse therapy promptly within 2 months of pregnancy, but there is a lack of evidence-based medical evidence; (2) All patients who have successfully given birth through GnRH pulse therapy and have no desire to have more children can terminate GnRH pulse therapy and change to sex hormone replacement therapy for maintenance; (3) After 24 months of use still patients without gonadal development should discontinue GnRH pulse therapy. (3) GnRH pulse therapy should be discontinued in patients with no gonadal development after 24 months of use. Children and adolescents are a special critical population that requires more rigorous adherence to scientific and standardized clinical practice. At present, clinical physical examination and laboratory tests lack more scientific quality control standards, which affect the overall standard and the quality of the analyzed data, therefore, long-term systematic follow-up and follow up are needed, which is more beneficial to the development of reasonable treatment plans in pediatrics. 8.GnRH pulse adjuvant therapy During GnRH pulse therapy, we should supplement the microelements required for pubertal development, eat a reasonable diet, exercise in moderation, and maintain a good lifestyle. GnRH pulse treatment increases testosterone, which can significantly increase bone density. The use of calcium or vitamin D supplements during GnRH pulse therapy may improve BMD. It has been reported in the literature that patients with IHH who have not been treated for a long time are more likely to develop disorders of glucose and lipid metabolism, which in turn increases the risk of cardiovascular disease. Domestic studies have found that the incidence of insulin resistance is higher in male patients with IHH. Some patients have low self-esteem, anxiety, depression and resistance at the time of consultation. Psychological interventions should be carried out in time to help patients build up confidence, better cooperate with treatment and obtain better results. However, there is still a gap in patient psychological intervention in China, which requires the active participation of psychologists.