The menstrual cycle of women is divided into follicular phase and luteal phase. The first day of menstruation is the beginning of a menstrual cycle, and the next menstrual period is the end of a menstrual cycle. The interval between the first day of menstruation is the number of days of the menstrual cycle, usually 23-35 days, with an average of 28 days. The period between the onset of menstruation and ovulation is the follicular phase. After the follicle ruptures and eliminates the egg, the corpus luteum is formed, so the period between ovulation and the next menstrual period is called the luteal phase. In the early menstrual period, estrogen levels are low and the hypothalamus and pituitary gland release large amounts of folliculopoietin (FSH) due to the absence of estrogen suppression. The sinus follicles in the ovaries (usually 2-8mm) are stimulated by folliculopoietin to grow and the follicles gradually grow. With the growth of follicles, follicular secretion of estrogen increases until the follicles reach 15-20 mm in diameter before ovulation, and estrogen levels reach 200-400 pg/ml. In the late follicular phase follicles grow rapidly, with an average daily growth of 2 mm after 14 mm in diameter. . The rapid rise in estradiol levels and high levels of estradiol stimulate the hypothalamus and pituitary gland, which release large amounts of luteinizing hormone (LH) and follicle stimulating hormone (FSH) in a short period of time, forming a pre-ovulatory gonadotropin peak, which generally lasts 24-36 hours from the beginning to the end of the gonadotropin peak, but the pattern of the LH peak, i.e., duration, rate of rise, peak height, and rate of decline are different and vary greatly, making it difficult to predict the timing of ovulation based on the pattern of LH. When follicles are stimulated by large amounts of LH to initiate the ovulation mechanism, the pattern of synthesis and secretion of sex hormones by granulosa cells in follicles rapidly changes, i.e., from an estradiol-secreting predominant to a progesterone-secreting predominant, with a rapid decrease in blood estradiol levels and a slow rise in progesterone. This change in follicular cells stimulated by LH is called luteinization. Usually on the first day after ovulation estrogen levels are around 40-100 pg/ml and progesterone around 1.0 ng/ml, then progesterone rises rapidly and estradiol also starts to rise, but the corpus luteum is predominantly progesterone-secreting. Clinically, gonadotropin-releasing hormone analogs (e.g. treprostin) can be injected to stimulate the pituitary gland to release gonadotropins, induce LH formation, and initiate the ovulation process and follicular luteinization. Chorionic gonadotropin (HCG) can also be injected to induce follicular luteinization and ovulation. Although only one sinus follicle grows and ovulates each month, there are multiple sinus follicles present in the ovary, both in the follicular and luteal phases, and sinus follicles of 2mm or more can be seen by vaginal ultrasound. 2. Disadvantages of superovulation during follicular phase Since the physiological follicle growth time is during the follicular phase, ovulation promotion has historically been started from the early follicular phase, i.e. from the 2nd-3rd days of menstruation with ovulation-promoting drugs. Exogenous ovulation-promoting drugs make the blood FSH level increase and induce multiple follicle development. The development of multiple follicles during the follicular phase causes a rapid increase in estradiol levels, which stimulates the hypothalamus and pituitary gland and induces the formation of an LH peak. If an LH peak occurs before the follicles are fully developed, it leads to damaged eggs, and the LH peak leads to ovulation when the follicles are mature. In order to improve the efficiency of in vitro fertilization-embryo transfer, ovulation-promoting drugs are often used to stimulate the growth of multiple follicles. Since multiple follicles can induce the formation of premature LH peaks and early ovulation, resulting in damaged eggs and failed egg retrieval, how to effectively suppress the appearance of premature LH peaks has been the top priority of ovulation-promoting during the follicular phase. From the advent of pituitary hyporegulation in the 1980s to the introduction of GnRH antagonists (e.g., Sizecap) in the 1990s, the aim has been to suppress the appearance of the premature LH peak. In order to prevent LH peaks, the superovulation technique of IVF became complex and expensive, with large amounts of drugs injected. Another unavoidable risk of follicular phase superovulation is the occurrence of ovarian hyperstimulation (OHSS). Since the mid-1980s until now, the descending-regulation superovulation technique has been widely used in China and abroad, and the incidence of severe OHSS has reached 1-4%, with severe cases of pleural fluid, ascites, hypoproteinemia, oliguria, renal failure, and even cerebral embolism, peripheral vascular embolism, and acute renal cortical necrosis, and there have been cases of death due to OHSS in China and abroad. Women with good ovarian reserve and women with polycystic ovary syndrome are at high risk for OHSS due to the large number of sinus follicles in the ovaries and the possibility of having more than 20 follicles after superovulation with descending regulation. Even if they do not use descending regulation, such as using Sizecap to suppress the LH peak, OHSS can also occur during follicular phase superovulation, but the incidence is lower than that of descending regulation superovulation. 3. History of the development of luteal phase superovulation Sinus follicles are always present in the ovaries of women of reproductive age, and small follicles of 2-8 mm can be seen on ultrasound in the luteal phase after ovulation, which is the basis of luteal phase superovulation. We did follicular phase ovulation promotion in a 41-year-old woman with occult ovarian failure in 2009. During the ovulation promotion, we found that progesterone reached 19ng/ml, which is equivalent to mid-luteal progesterone level. Since we saw follicles growing in the ovary, we continued to use ovulation-promoting drugs and the follicles grew smoothly and miraculously we got 7 precious eggs, which were fertilized in vitro to get 2 high-quality embryos, which were frozen and preserved They were frozen and preserved. Two months later, the two embryos were thawed in a natural cycle, and the twin pregnancies were transferred and two healthy babies were delivered at full term. This case has inspired us that the embryos obtained in high progesterone state have the potential to develop. It was assumed that the embryos obtained by luteal phase ovulation also have developmental potential, which stimulated our interest in luteal phase ovulation. The initial idea was to use luteal phase ovulation in women with low ovarian reserve, because some women of advanced age or with low ovarian reserve tend to ovulate small follicles, and follicular phase ovulation is mostly single follicle development, and it is very difficult to suppress the LH peak, but we observed that some patients could see several 2-8 mm sinus follicles after ovulation, and if these seeds could be allowed to grow and mature by ovulation, it would be an additional benefit for these patients. If these seeds could be brought to maturity by ovulation, it would give these difficult patients an additional hope of success. However, subsequent clinical studies have found that ovulation during the luteal phase with exogenous gonadotropins (e.g. HMG) alone is difficult, as the luteal phase follicles are not sensitive to gonadotropin stimulation, follicle development is delayed, and ovulation time exceeds 20 days. Therefore, there is no advantage in using gonadotropins alone to promote ovulation during the luteal phase. Foreign studies have also ended in failure. In order to achieve success in luteal phase ovulation, we must find ways to improve the sensitivity of follicles to HMG. After continuous theoretical analysis and repeated review of the first successful luteal phase ovulation case, in early 2012, I noticed the first case where letrozole was used during follicular phase ovulation. Letrozole is an aromatase inhibitor that inhibits the conversion of androgens to estrogens in the follicular granulosa cells, resulting in increased androgen levels in the granulosa cells. The right amount of androgens can promote the synthesis of FSH receptors and increase the sensitivity of the follicles to ovulation-promoting drugs. Perhaps letrozole is the key regulator of luteal phase ovulation. Subsequently, letrozole combined with HMG was used for luteal phase ovulation in a senior woman who failed follicular phase ovulation, and the ovaries responded very well with 6 good quality embryos! After two months of cryopreservation 2 embryos were transferred in a natural cycle and pregnancy was successful. This result was in full agreement with the theoretical analysis, and more cases subsequently confirmed that letrozole combined with HMG during the luteal phase greatly improved follicular responsiveness, with an average time to ovulation of 12 days, which is equivalent to the use of gonadotropin drugs in a descending regimen of superovulation. More observations also prove that the embryo transfer success rate obtained from luteal phase ovulation is high and even exceeds that of follicular phase ovulation, so what is the mechanism? 4. Luteal phase superovulation overcomes the drawbacks of follicular phase superovulation In subsequent studies, we found that luteal phase superovulation does not result in spontaneous LH peaks and the problems that plagued follicular phase superovulation no longer exist! Thus luteal phase superovulation becomes quite simple, no medication to prevent early ovulation is needed, monitoring frequency is greatly reduced, and patient visits are less frequent. Since the pituitary gland is suppressed, LH levels are kept at physiological levels, resulting in high egg quality, good embryo quality and high embryo implantation rates. What surprises us even more is that luteal phase superovulation does not result in OHSS! Even if more than 20 eggs are obtained, no abdominal distension symptoms appear. Why is there no LH peak during luteal phase superovulation? Our study found that the corpus luteum itself is the key factor that inhibits the appearance of LH peak and prevents the occurrence of OHSS. Although the detailed molecular mechanism is still unclear, we are certain that the presence of corpus luteum is a necessary condition for luteal phase superovulation, without which the two major advantages of luteal phase superovulation would not occur. 5. Luteal phase superovulation is a conventional superovulation protocol for in vitro fertilization-embryo transfer Although our initial research on luteal phase ovulation was aimed at increasing a chance of egg acquisition in difficult patients, given the various advantages of luteal phase superovulation, it is clear that this superovulation protocol is suitable for all patients and is an ideal superovulation protocol that is simple, convenient, safe, low cost and efficient. Two major problems that have plagued the reproductive community for decades: premature LH peak and OHSS have disappeared because of the advent of luteal phase superovulation technique, which is one of the important advances in the history of ovulation promotion. In addition, luteal phase superovulation challenges the mechanism of follicular development and atresia, sheds new light on the function of the corpus luteum, and provides important inspiration for the study of reproductive endocrinology. 6. Preparation for luteal phase superovulation Patients who wish to undergo luteal phase superovulation need contraception after menstruation to prevent unintended pregnancy. An unplanned pregnancy during luteal phase superovulation may lead to severe ovarian hyperstimulation syndrome, which is the same mechanism as the late ovarian hyperstimulation that occurs in pregnancies after embryo transfer in conventional superovulation cycles, and is the result of superovulation + endogenous HCG stimulation of the ovaries, so patients preparing for luteal phase superovulation must use strict contraception before ovulation and should not take any chances. We have several cases of unplanned pregnancy during luteal phase ovulation, all of which were caused by the belief that they were unlikely to get pregnant and did not insist on strict contraceptive measures, including patients with severe oligospermia and 7 failed transplants from outside hospitals. Patients who are ready for luteal phase superovulation can monitor ovulation by taking basal body temperature or measuring urinary LH. It is better to take basal body temperature in patients with long menstrual cycles, or to start measuring urinary LH when they feel clear leucorrhea, and to visit the clinic before and after ovulation if there are multiple sinus follicles of 2-8 mm in the ovaries on ultrasound. Patients with good ovarian reserve are particularly suitable for luteal phase superovulation with an implantation rate of 42% per embryo! Patients with ovulation disorders can start with letrozole to induce follicular growth and start luteal phase superovulation after ovulation. On the first day, the LH peak is positive and note the T-line, which is relatively deep; on the second day, the LH peak is slightly weakened and note the T-line; on the third day, the LH peak is close to disappearing and the T-line is almost invisible; after the LH peak subsides, luteal phase ovulation can be started. Luteal phase superovulation can be used in combination with follicular phase superovulation, i.e. follicular phase superovulation is done first, and ovulation promotion is continued after egg retrieval to increase the chance of egg acquisition. 7. Menstrual pattern after luteal phase superovulation Luteal phase superovulation will usually bring about menstruation in a week or so after egg retrieval. If you have not used Angioplasmin before egg retrieval, your menstruation will come earlier and your first menstruation will be caused by the luteal receding before ovulation promotion. After the night injection, the follicle should be luteinizing and forming the second batch of corpus luteum, the second batch of corpus luteum has not yet subsided when the first menstruation occurs, the progesterone in the body is maintained at a high level, progesterone inhibits the growth of the endometrium, so the menstruation is not clean, or it comes again a few days after clean, but the amount is small, the second bleeding is the result of the second batch of corpus luteum subsiding, from the endocrinological point of view, the second bleeding is the result of the corpus luteum completely subsiding, it is The first menstruation in the true sense of the word (the luteal receding, resulting in a drop of estrogen and progesterone in the body, causing the endometrial lining to peel off, called menstruation). Frozen embryo transfer should be performed in the next menstrual cycle after the second bleeding, if the cycle is normal ovulation monitoring should be started on the 12th day of menstruation, if the menstrual cycle is prolonged, visit on the 3rd day of menstruation, refer to my article: Is hair natural – endometrial preparation for frozen embryo transfer.