Hypogonadotropic hypogonadism (HH) in women is a group of disorders in which the hypothalamus or pituitary gland is diseased, resulting in low ovarian function. Estrogen and progesterone replacement therapy can promote and maintain the development of secondary sexual characteristics and artificial menstrual cycles in women. For patients with fertility requirements, gonadotropin-releasing hormone or gonadotropin supplementation can induce follicular development, ovulation, and even pregnancy. This article focuses on the progress of ovulation induction therapy in women with HH. Hypogonadotropic hypogonadism (HH) is a condition in which hypogonadotropic hormone (GnRH) or luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels are reduced in the hypothalamus or pituitary gland due to congenital or acquired factors. The main manifestations are complete or partial absence of secondary sexual characteristics, hypogonadism, amenorrhea, and infertility. Congenital HH is also known as idiopathic hypogonadotropic hypogonadism (IHH), and most research suggests that the true cause of IHH is related to genetic mutations. The overall incidence of IHH (normosmic idiopathichypogonadotropic hypogonadism, nIHH) is about l/(100,000-101,100,000), with a male to female ratio of about 5:1. The treatment of female HH is different from that of male due to the inherent physiological cycle of women. (1) Promotion and maintenance of secondary sex characteristics: Exogenous estrogen and progestin replacement can be used to promote the development of secondary sex characteristics in prepubertal females. Low-dose estrogen is first used to promote breast development, induce uterine enlargement and endometrial hyperplasia, followed by sequential treatment with progestin to form an artificial cycle. In addition to promoting and maintaining female secondary sexual characteristics, estrogen and progestin therapy are also beneficial in increasing bone density in patients. (2) Ovulation induction: If the patient has a fertility requirement, ovulation induction is required, including both GnRH pulse infusion and exogenous injections of gonadotropins (LH, FSH). The frequency and magnitude of sex hormone secretion differs in women at each time of the menstrual cycle, whereas in men sex hormone secretion occurs at a relatively constant frequency and magnitude, so ovulation induction therapy for women has its own special features compared to fertility treatment for men. Ovulation induction therapy with gonadotropins Human chorionic gonadotropin (hCG) and LH have similar B subunits and can bind to LH receptors to exert LH-like effects: urinary gonadotropin (hMG) is a gonadotropin extracted from the urine of menopausal women and contains two biologically active components, FSH and LH (1:1), of which FSH is the main component to promote follicle development. When used to induce ovulation in women, hMG is usually started at a low dose (37.5 IU/d intramuscularly) and later adjusted by ultrasound monitoring of follicular development (75 to 150 IU/d). Ideally, only a single dominant follicle should be induced. If the dominant follicle is larger than 18 mm in diameter, hCC (5,000-10,000 IU intramuscularly) or recombinant hCG (thCG, 250 μg subcutaneously) or recombinant human LH (thLH, 25,000-30,000 IU intramuscularly) can be administered to promote ovulation. Post-ovulatory luteal function is maintained with 1-2 doses of hCG (1500-25001 U/3-4 d). The cumulative pregnancy rate after 6 cycles of this regimen (survival analysis) is 89%. The incidence of severe ovarian hyperstimulationsyndrome (OHSS) is approximately 1%, while the incidence of multiple pregnancies can be as high as 30%. rhLH and rhFSH are high purity gonadotropin preparations synthesized by genetic engineering technology, which have the advantages of high specificity, low adverse effects, less likely to produce antibodies in vivo and long duration of action. In recent years, thFSH has been used to promote follicular development but not to stimulate the ovaries to produce sufficient estradiol, while 75 IUthLH and 150 IU thFSH can achieve satisfactory follicular development (>18 mm in diameter), suggesting that LH also plays an important role in follicular development. In the study by Kaufmann et al, the use of high-dose hCG to induce ovulation resulted in satisfactory pregnancy outcomes, but there was still a risk of multiple pregnancies (18 010 pregnancies per treatment cycle, 26% of which were multiple) and mild to moderate OHSS in 7.9% of patients. In a study by Kaufmann et al, rhLH (75 IU) and rhFSH (75-225 IU) were administered simultaneously to 31 female HH patients for a total of 54 treatment cycles. 27 patients (87.1%) achieved satisfactory follicular development, of whom 20 (74.1%) became pregnant and 16 (59.3%) successfully maintained a clinical pregnancy. CnRH pulse pump therapy In normal women, the hypothalamus secretes GnRH in pulses, which acts on the pituitary gland to produce gonadotropins (LH and FSH), and the levels of LH and FSH fluctuate during the different phases of the menstrual cycle. The faster the frequency of GnRH pulses (less than 60 min), the more the pituitary gland secretes LH, whereas the slower the frequency of CnRH pulses (>120-180 min), the more the pituitary gland secretes FSH. In the early follicular phase, the CnRH pulse frequency is about 1/120-1/90 min, and FSH secretion is dominant, while estradiol and inhibin levels are low. After ovulation, the ovaries mainly produce progesterone, which in turn increases hypothalamic opioid activity and slows GnRH pulse secretion (1/5-1/3 h), promoting pituitary synthesis of FSH, while luteal secretion of estradiol and inhibin inhibits FSH release, so that FSH reserves increase. If conception does not occur, the corpus luteum atrophies and the levels of estradiol, inhibin and progesterone decrease, which reduces the negative feedback inhibition of FSH and increases the release of the stored FSH. As progesterone levels decline, the frequency of GnRH pulses gradually accelerates and the next menstrual cycle is initiated. Therefore, in patients with HH caused by hypothalamic lesions, GnRH pulse infusion therapy is the closest to the physiological state. Several studies have shown that GnRH pulse infusion therapy can lead to successful ovulation and even pregnancy in women with HH, but only in patients with some pituitary function. In 1990, the FDA approved the use of GnRH pulse infusion for ovulation induction in patients with hypothalamic amenorrhea, and many studies have been conducted on this topic. Theoretically, female HH patients should adjust the frequency and dose of pulse infusion according to their menstrual cycle, or even suspend pulse infusion in order to experience menstrual flow. In the study by Manin et al, ovulation was induced in female HH patients (including nIHH, Kallmann’s syndrome and hypothalamic amenorrhea) by intravenous pulsed infusion of GnRH at a frequency that was based on the physiological secretion pattern of CnRH in the normal female menstrual cycle: the frequency of GnRH secretion in the first week was approximately 1/90 min, simulating the early follicular phase of the female, mainly promoting FSH secretion. In week 2, the frequency is increased to 1/60 min to create an endogenous LH peak to promote ovulation. until the onset of menstruation and the next cycle. A pulse dose of 75 ng/kg (approximately 3-4 μg) of GnRH produces estradiol and progesterone levels similar to those of normal women, with an ovulation rate of 95%. In patients who do not respond well, increasing the pulse dose can still induce ovulation. A life table analysis corrected for termination of treatment or pregnancy showed a cumulative pregnancy rate of 94% over 6 treatment cycles in 21 patients (the cumulative pregnancy rate in normal women is approximately 80% over 6 months), with only one case of multiple pregnancy. Abel et al. retrospectively analyzed 37 female IHH patients treated with a GnRH pulse infusion similar to that described above and showed an ovulation rate of 60% in the first treatment cycle, which increased to 86% overall with longer treatment cycles or increased pulse doses. In view of the complexity of adjusting and monitoring the physiological frequency, some authors have also achieved satisfactory ovulation rates with fixed 90 min or 60 nun GnRH pulse cycles. The pregnancy rate was as high as 33%. In China, Sun Shuyue et al. treated 6 women with IHH with subcutaneous administration of GnRH pulses (Gonarelin) with a fixed pulse cycle of 90 min and an initial pulse dose of 10 μg, followed by dose adjustment according to LH and FSH levels. At 24 weeks of treatment, a significant increase in the size of the uterus and ovaries, thickening of the endometrium, and an increase in the number of follicles with a dominant follicle >10 mm in diameter were observed. 5 patients had menstrual periods with regular menstrual cycles. It is believed that in addition to the positive regulation of LH and FSH secretion by the pituitary gland by GnRH pulses, they can also be regulated by the negative feedback of hormones secreted by target organs. To date, the comparison of ovulation rates, pregnancy rates and the incidence of ovarian stimulation and multiple pregnancies in women with HH treated with fixed versus physiological frequency CnRH pulses is inconclusive and still needs to be validated by the results of a large randomized controlled study. A retrospective analysis of 283 female HH patients treated with GnRH pulse pumps at 24 centers in France suggested that the chance of conception per GnRH pulse infusion cycle was approximately 25%, and the average number of treatment cycles required to achieve pregnancy was 2.8. The incidence of multiple pregnancies after GnRH pulse pump treatment was 8.8% and no severe OHSS was observed. Increasing the dose of GnRH pulse treatment was also effective in patients with GnRH receptor gene mutations. Abel et al. concluded that the effect of GnRH pulse infusion (mimicking physiological frequency) in women with IHH may be related to the genotype of the patient, with GnRHR, PROKR2 and FGFR1. PROKR2 and FGFR1 mutations were less effective, but normal ovulation could be achieved by increasing the dose of CnRH pulses. As for the choice of GnRH pulse dosing, the rapid onset of peak gonadotropin and its rapid fall to baseline levels can be observed with higher ovulation rates with intravenous dosing, while subcutaneous dosing is more convenient and has a lower incidence of infection than intravenous dosing due to delayed absorption and delayed rise and fall of gonadotropin. Currently, subcutaneous administration is used for patient convenience, and if ovulation is not induced, intravenous administration is used instead. Comparison of different ovulation induction modalities Exogenous gonadotropin injections and GnRH pulse infusions have shown satisfactory ovulation and pregnancy rates in the induction of ovulation in female HH patients. Martin et al. applied exogenous gonadotropin replacement and CnRH pulse infusion to induce ovulation in female HH patients and found similar ovulation and pregnancy rates per patient per cycle in both groups, but the cumulative probability of pregnancy after 6 cycles of treatment was lower in the former method (720/0) than in the latter method (96%) using life table analysis. The incidence of multiple pregnancies was higher in the gonadotropin-treated group than in the CnRH pulse infusion group (14.8% vs. 8.3%), and although no severe OHSS occurred, multiple follicles and more pronounced ovarian enlargement and elevated hormone levels were observed. The detection rate of HH has gradually increased in recent years with the improvement of medical treatments. The need for fertility in male and female HH patients is also increasing. The complexity of the regulation of hormone levels in the female inherent cycle makes the treatment of female HH more difficult. 1. Exogenous estrogen and progestin replacement can promote and maintain the development of female secondary sex characteristics, but does not help ovulation. Exogenous gonadotropin injections have been very successful in inducing ovulation in female HH patients, but the incidence of multiple pregnancies and ovarian hyperstimulation has increased accordingly. 2. GnRH pulse pump therapy is closer to the physiological state for HH patients with certain pituitary function, which can promote the production of endogenous gonadotropins and estrogen and progesterone, and establish a feedback mechanism similar to that of normal women, simulating the physiological state to induce ovulation and minimizing the incidence of adverse effects. Good ovulation and pregnancy rates have been achieved with either near physiological or fixed frequency administration, but the effects of both modalities on treatment outcomes need to be further compared in large randomized controlled studies. In some patients who do not respond well to conventional GnRH dosing, increasing the pulse dose may still induce ovulation. Therefore, GnRH pulse pump therapy may be preferred for female HH patients with fertility needs who have essentially normal pituitary function. If technical problems are limited or if severe hypopituitarism is present, exogenous injectable gonadotropin therapy may be considered.