The use of drugs and drug combinations to stimulate the ovaries is essential to obtain a certain number of high-quality eggs and to increase the clinical pregnancy rate in IVF. The evolution of ovarian stimulation protocols, also known as superovulation protocols, has accompanied the development of IVF fertility technology, reflecting the ongoing process of human understanding and transformation of the world. The first generation of ovarian stimulation regimens Early HMG ovulation protocols were characterized by early ovulation drugs that promoted multiple follicle development but also led to early endogenous LH peaks, high cycle cancellation rates and low pregnancy rates. The use of animal pituitary gonadotropins and pregnant horse serum to promote ovulation began in the 1830s, but was discontinued due to allergic reactions to xenobiotics. human pituitary-derived gonadotropins were introduced in the 1950s, but did not meet clinical needs in sufficient amounts and, more importantly, were found to cause the fatal Ruanovirus disease and CJD disease, a long latency neurological disorder, and were also discontinued In the early 1960s, human menopausal gonadotropin (hMG) was of very low purity and had a large number of impurity proteins. In fact, the early work of IVF applied hMG+HCG to promote ovulation, and although several follicles were obtained, no clinical pregnancy was obtained due to the shortened luteal phase caused by the drugs and the absence of effective luteal support drugs. Instead, a natural cycle of egg retrieval completely without drug stimulation resulted in the birth of the world’s first IVF. During this period, clomiphene was also used to obtain more follicles. the CC+hMG prolotherapy regimen resulted in a clinical pregnancy rate of 25%. However, increased LH levels in the late follicular phase led to decreased egg quality, early ovulation, and cycle cancellation rates of 5-20%. Second generation ovarian stimulation regimen Application of GnRH agonists and antagonists in the era of pituitary descending regulation Features The clinical application of GnRH agonists is a milestone in superovulatory treatment, and the GnRH-a+rFSH descending regulation long regimen has become the classic ovarian stimulation regimen commonly used in clinical practice today. the GnRH antagonist regimen, combined with the GnRH-a trigger, reduces the incidence of OHSS and is simple to treat. with a strong development trend. 1980s: The era of GnRH agonists plus urinary-derived HMG In order to stop the early onset of endogenous LH peaks, Porter applied GnRH-a analogues to the superovulatory regimen in 1984, which became a milestone in superovulatory treatment. The simultaneous purification process resulted in increased purity of hMG and tended to reduce the LH content of the drug for purified FSH preparations. The regimens of GnRH-a combined with HMG were generated according to the time of down regulation: ultra-short regimen, short regimen, and long regimen. The short and ultra-short regimens use the initial stimulatory effect of GnRH-a to promote follicle recruitment and maintain low pituitary gonadotropin levels during the second half of the regimen, while exogenous gonadotropin (Gn) is given to promote follicle development. However, due to the early stimulatory effect, which can elevate endogenous LH early on and affect egg quality and uneven follicle development, the application of these two regimens has now been significantly reduced. The long regimen involves the administration of GnRH-a analogs during the menstrual or luteal phase, where the pituitary gland is desensitized to create a hypogonadotropic state, followed by exogenous Gn to promote follicle development. This regimen of synchronized follicle development without endogenous LH peaks greatly improves egg quality and clinical pregnancy rates, and facilitates scheduling routines. 1990s: the era of GnRH agonists plus urine-derived/recombinant FSH In this era, highly purified FSH preparations (FSH-HP) were widely used in the clinic, with little variation between drug batches, subcutaneous injection and good ovulation-promoting effects, but urine-derived preparations had limited sources of raw materials, poor quality control and could not avoid cross-contamination, etc. Genetically recombinant FSH preparations ( The recombinant FSH preparation ( rFSH) has entered the historical stage and played an important role. The GnRH-a+rFSH descending regimen can effectively suppress endogenous LH peaks, obtain synchronous development of multiple follicles, achieve good egg quality, high and stable pregnancy rates, and is a classical ovarian stimulation regimen commonly used in clinical practice. After 2000: the era of massive application of GnRH agonist regimens and slow development of antagonists While GnRH agonist regimens became the mainstream regimen and were used in large numbers, the role of LH in ovulation promotion was gradually discovered, and follicle development was affected by excessive LH suppression. GnRH antagonists can compete for GnRH receptors and rapidly inhibit LH production, which can be used in the late stage of superovulation to suppress the pituitary gland and shorten the treatment cycle, making the treatment more comfortable and convenient for patients. Combined with GnRH-a trigger, it reduces the incidence of OHSS. It has become the mainstream ovulation promotion protocol in Europe, Australia and other countries. In China, the development has been slow due to the insufficient supply of antagonist drugs, but now there is a trend of gradually increasing clinical application. Third-generation ovarian stimulation protocol Non-decreasing regulation ovulation promotion protocol based on follicular wave theory Features The return of non-decreasing regulation protocol is a progress rather than a regression in understanding that ovarian stimulation protocol will be more humane and simple without the cost of pregnancy rate reduction. In recent years, with the further understanding of the reproductive endocrine follicular wave theory, ovarian cycle, and menstrual cycle based on the belief that ovulation can be promoted at any time as long as there is an FSH-recruiting follicular wave. Furthermore, the development of ultrasound monitoring, serum hormone assays and laboratory techniques have provided for simpler and more effective ovulation protocols. There is also a greater concern for patient comfort and cost effectiveness of ovulation treatment. Thus the natural cycle, clomiphene/letrozole + HMG microstimulation regimen has come back to our attention. Follicular phase combined with luteal phase ovulation, progestinized ovarian stimulation protocols, suggest the possibility of progesterone replacing GnRH-a to suppress LH peaks as a new ovulation strategy. These non-descending regulated ovulation regimens with milder ovarian stimulation and fewer drugs are in line with physiological hormone levels, and although they are not mainstream regimens, their use has gradually increased in recent years, especially in patients of advanced age and with declining ovarian function.