The corpus luteum is the main source of steroid hormones, and normal luteal function is an important part of the process necessary to maintain pregnancy. Luteal insufficiency can make it difficult to maintain a normal pregnancy. Luteal support and progesterone supplementation are designed to address this problem. 1. The concept of corpus luteum and luteal insufficiency Luteal insufficiency occurs in 100% of ovulation-promoting cycles. 1.1 Concept of corpus luteum The corpus luteum is a vascularized, temporary endocrine gland formed by the residual follicles after ovulation and consists of steroid-producing cells (granulosa lutea cells, membrane lutea cells) and non-steroid-producing cells such as fibroblasts, immune cells, and vascular endothelial cells. The main function of the corpus luteum is to synthesize steroid hormones, including progesterone, estrogen and androgen. Among them, progesterone is the steroid hormone essential for the establishment and maintenance of pregnancy. Progesterone binds to endometrial progesterone receptors to convert the proliferating endometrium to the secretory phase, preparing the fertilized egg for implantation and development, while inducing endometrial interstitial cells to proliferate and differentiate, and promoting endometrial metaplasia. During pregnancy, progesterone can raise the excitation threshold of uterine smooth muscle and inhibit uterine contraction, and also has certain immune effects. In summary, a certain level of progesterone is essential for the maintenance of pregnancy. Removal of the corpus luteum before 7 weeks of gestation can lead to miscarriage, while the supplementation of exogenous progesterone can maintain the pregnancy. Normal mid-luteal plasma progesterone concentrations ≥15 (6-30) μg/L, <10 μg/L suggest luteal insufficiency, and ≤5 μg/L suggest anovulation. Luteal secretion of estrogen is not a hormone necessary to maintain pregnancy, but it has an important role in maintaining progesterone levels and promoting normal endometrial secretion transformation. Insufficient luteal secretion of estrogen can lead to infertility or early pregnancy miscarriage. In addition to steroid hormones, the corpus luteum also synthesizes and releases a large number of protein hormones, including relaxin, contractin and inhibin. After ovulation in the natural menstrual cycle, if there is no pregnancy, the corpus luteum formed is called menstrual corpus luteum, which starts to degenerate 9-10 days after ovulation and remains for about 14 days in total, gradually being replaced by connective tissue to form white bodies. The luteal life span is significantly shortened during the ovulation cycle and will be more pronounced if gonadotropin-releasing hormone analog (GnRHa) is applied to induce egg maturation. If the egg is fertilized and pregnancy is successful, the corpus luteum continues to grow in response to human chorionic gonadotropin (hCG) secreted by embryonic trophoblast cells and becomes the corpus luteum of pregnancy. In the 7th to 9th week of pregnancy, the placenta will replace the corpus luteum to produce steroid hormones. 1.2 The concept of luteal insufficiency Luteal insufficiency was first introduced by Jones in 1949 and refers to poorly developed corpus luteum after ovulation, which secretes insufficient progesterone or premature degeneration of the corpus luteum, resulting in reduced endometrial secretory responsiveness and is closely associated with infertility or miscarriage. The etiology of luteal insufficiency is still not fully understood, and the common clinical methods used to determine it include basal body temperature measurement, endometrial biopsy and determination of mid-luteal progesterone level. At present, it is believed that luteal insufficiency can be diagnosed if the average value of serum progesterone level is <15μg/L when measured at the same time on day 5, day 7 and day 9 after ovulation. The incidence of luteal insufficiency in women of reproductive age and natural cycles is 3% to 10%. In contrast, in ovulation-promoting cycles, the incidence of luteal insufficiency is almost 100% due to the simultaneous development of multiple corpus luteum, which secretes far more estrogen and progesterone than the physiological dose and inhibits LH secretion through negative feedback. 2. Indications and contraindications for luteal support and progesterone supplementation 2.1 Indications (1) In vitro fertilization/intracytoplasmic single sperm injection-embryo transfer (IVF/ICSI-ET) and other methods of fertility treatment with controlled ovarian stimulation, with a certain degree of endogenous luteal insufficiency after embryo transfer. (2) After ovulation in a natural cycle, freeze-thaw embryo transfer (FET) is performed, and some women may have their own luteal insufficiency. (3) ovulation promotion cycle line FET, there is a potential endogenous luteal insufficiency. (4) estrogen and progestin drug replacement cycle (artificial cycle) FET, using exclusively exogenous estrogen and progestin drugs to replace luteal function. (5) History of previous recurrent miscarriage. (6) Pre-eclampsia miscarriage. (7) Preterm labor. 2.2 Contraindications (1) Patients with suspected or existing arterial or venous thrombosis, patients with previous history of phlebitis, stroke, etc. should be used with caution; (2) Patients with malignant tumors of the breast or hormone-dependent tumors of the reproductive system, with clear contraindications to estrogen therapy; (3) Patients with progesterone allergy. Commonly used drugs for luteal support Currently, the commonly used drugs for luteal support include: progesterone, hCG, estrogen and GnRHa. hCG is no longer recommended as a routine drug for luteal support in ART ovulation cycles. 3.1 Luteinizing hormones Luteinizing hormone is a natural progestin secreted by the ovarian corpus luteum and placenta. Progesterone analogs are divided into natural progestins and synthetic progestins. Progesterone is the main progestin currently used for luteal support. Synthetic progestins are mostly progesterone or testosterone derivatives, both of which have androgen-like effects and may increase the risk of birth defects in the offspring. 1999 US FDA concluded after a detailed evaluation that pregnant mothers exposed to progesterone or 17α-hydroxyprogesterone caproate (17α-OHPC) did not deliver male or female offspring with an increased rate of birth defects. The commonly used routes of administration are intramuscular, transvaginal and oral, and it is important to note that the absorption and metabolism processes in the body vary by route of administration. Intramuscular progesterone injection Intramuscular progesterone is an oil-based progesterone, which is rapidly absorbed after injection, without hepatic over-effects and with high bioavailability. The commonly used dose is 20-100mg/day. The advantages of intramuscular progesterone include: precise efficacy, low price, and is the traditional drug for luteal support in human assisted reproductive technology (ART). Its disadvantages include: high incidence of adverse reactions, possible allergic reactions, inconvenience of daily intramuscular injection, pain and irritation at the injection site prone to the formation of local hard nodes, and even the occurrence of local sterile abscesses and sciatic nerve injury, and longer time required for the absorption and recovery of local hard nodes and sterile abscesses. Progesterone for vaginal use Progesterone for vaginal use is currently the only preparation that can replace intramuscular progesterone in ART progesterone support. The main common dosage forms are progesterone extended-release gel and micronized progesterone capsules. Vaginal progesterone mainly works locally in the uterus. After administration, the vaginal epithelium rapidly absorbs and diffuses to the cervix and uterine body, and completes the diffusion from the endometrium to the myometrium, and the "uterine first-pass effect", the progesterone concentration in serum is significantly lower than that of intramuscular progesterone, which can reduce systemic adverse effects and has the same efficacy, It is easy to use and painless, so it has become the first choice for ART luteal support in some countries. Commonly used dose: progesterone extended release gel 90mg/day; micronized progesterone capsules 300-800mg/day (given in 3-4 times). In clinical application, compared with intramuscular progesterone, vaginal progesterone has a higher incidence of vaginal bleeding during the luteal phase than intramuscular progesterone, but does not affect ART pregnancy outcome, while estrogen supplementation reduces the incidence of vaginal bleeding but does not change pregnancy outcome. Oral progesterone Oral progesterone formulations, including micronized progesterone capsules and dydrogesterone, both have first-pass effects, and most of the active ingredients are metabolized and broken down by the liver, resulting in low bioavailability. Compared with micronized progesterone capsules, dydrogesterone is highly selective for progesterone receptors, has less adverse effects, is easily absorbed orally, has higher bioavailability, and is more convenient and better tolerated with less hepatic load. Moreover, its metabolites still have progestational activity, with good side effects and good patient compliance. The effective dose is 10 to 20 mg/day. It should be noted that oral dydrogesterone does not alter the original serum progesterone level, and there is a lack of evidence-based medical evidence on the effectiveness of dydrogesterone alone in ART luteal support. 3.2 hCG hCG is a glycoprotein-like hormone secreted by placental trophoblast cells. hCG is highly homologous to the LH molecule and acts on LH receptors instead of LH, and therefore has the function of inducing egg maturation, causing luteinization and luteal support. The presence of ovarian corpus luteum is a prerequisite for hCG to be used for luteal support. Meta-analysis showed that in ART luteal support, the application of hCG did not have an advantage over the application of progesterone in terms of clinical pregnancy rate, persistent pregnancy rate, birth rate and miscarriage rate, but significantly increased the occurrence of ovarian hyperstimulation syndrome (OHSS) and may interfere with pregnancy test results, requiring at least 5-7 days of discontinuation before reexamination. Therefore, hCG is no longer recommended as a routine agent for luteal support in ART ovulation cycles. 3.3 Estrogens The main estrogens in women are estradiol (E2), estriol (E3) and a small amount of estrone (E1), most of which are secreted by the ovaries, with E2 being the most active and important. After ovulation, estrogen and progesterone work together to transform the proliferative endometrium to the secretory phase, which is conducive to embryo implantation and implantation. Estrogen increases the blood supply to the uterine base and promotes the proliferation of uterine smooth muscle cells, which thickens the uterine base and facilitates the development of embryos. Estrogen also increases blood flow to the uteroplacenta and promotes the formation of placental blood vessels, providing optimal gas and material exchange for the fetus, thus ensuring normal fetal development. However, it is still controversial whether it is beneficial to continue adding estrogen in cases where the estrogen level of ART pregnancy aid is normal or even too high. Currently, the main estrogenic drugs available for fertility-related treatment in China are estradiol valerate and 17β-estradiol, which can be administered orally, vaginally and transdermally in three different ways. Oral administration is rapidly and completely absorbed and convenient, but there is a hepatic first pass effect that affects bioavailability. Vaginal administration has no hepatic first-pass effect, but estradiol valerate is less absorbed by vaginal administration, so transvaginal administration is recommended. Transdermal administration avoids the hepatic first-pass effect or increased hepatic load of oral drugs. The luteinizing support effect of estrogens is still controversial, and in patients of advanced age, the risk of thrombosis needs to be guarded. Abnormal liver function has been reported with high doses. 3.4 GnRHa The effectiveness of GnRHa as an adjunct to luteal support remains controversial, and the mechanism of action is not fully understood. It is currently believed that GnRHa can promote the secretion of LH from the hypothalamus pituitary gland to act on the corpus luteum and promote the secretion of estrogen and progesterone, which in turn promotes the implantation and development of the embryo.GnRHa for luteal support does not increase the risk of OHSS and is closer to the natural cycle, but it is not suitable for patients with suppressed pituitary function such as those using long-acting and long protocols for descending regulation. Currently, the commonly used drugs are treprostinil acetate, buserelin acetate, leuprolide acetate, etc. 4. Choice of luteal support drugs 4.1 Luteal support in ART During luteal support, serum hCG levels need to be monitored to help determine chorionic activity, and ultrasound is performed to monitor embryonic development without monitoring serum progesterone levels and their changes. The application of controlled ovarian stimulation in ART, which suppresses endogenous luteinizing hormone (LH) peaks, and high doses of hCG to induce final maturation of oocytes, which inhibits endogenous LH secretion through negative feedback, can both lead to endogenous LH deficiency, resulting in low progesterone levels in the luteal phase. In addition, loss of granulosa cells during egg retrieval results in fewer hormone-producing cells in the luteal phase. All of the above may affect estrogen and progesterone secretion, decrease embryo implantation rate and clinical pregnancy rate, and increase miscarriage rate. The most commonly used drugs in clinical practice are progesterone drugs, including intramuscular, vaginal and oral dosage forms. Intramuscular progesterone is a traditional drug with reliable efficacy, cheap price and common application. When comparing vaginal progesterone with intramuscular progesterone, there is no difference in the effect of progesterone support, and the inconvenience and side effects caused by intramuscular injection are avoided. Oral progesterone is quite inadequate for luteal support during the egg retrieval cycle and is not recommended alone. Luteinizing support is generally recommended to be started immediately after egg retrieval and no later than the day of transplantation. After confirmation of intrauterine pregnancy, the dosage can be gradually reduced until discontinuation at 10 to 12 weeks of gestation. Since not all luteal support drugs show elevated serum progesterone levels, it is necessary to monitor serum hCG levels to help determine chorionic activity and to perform ultrasound to monitor embryonic development without monitoring serum progesterone levels and their changes during the course of the drug. 4.2 Luteal support in pre-eclampsia and recurrent miscarriage There is no evidence to support that routine administration of luteal support in early and mid-trimester reduces the incidence of miscarriage. It is currently believed that 50% of miscarriages, especially early-trimester miscarriages, are due to embryonic chromosomal abnormalities. Therefore, patients with pre-eclampsia miscarriage should be advised to rest and avoid emotional stress on the basis of adequate explanation. There is still an international controversy on whether progesterone supplementation is needed for preterm miscarriage, and there is no sufficient evidence to support that progesterone supplementation can reduce the chance of eventual miscarriage in patients with preterm miscarriage. Therefore, the need for progestin supplementation in this group of patients requires a combination of patient age, physical examination and laboratory findings. If the vaginal bleeding stops and ultrasound indicates a viable embryo after luteal support is given, the pregnancy may continue. If clinical symptoms worsen, ultrasound indicates embryonic dysplasia, and hCG continues not to rise or even to fall, miscarriage is considered inevitable and the pregnancy should be terminated. It is still controversial whether to give luteal support or progesterone supplementation to patients with unexplained recurrent miscarriage, and there is no evidence to support that routinely giving them luteal support in early and mid-trimester can reduce the occurrence of miscarriage. 4.3 Progestins in the prevention of preterm labor There has been an increasing number of studies confirming the effectiveness of certain specific types of progestins in the prevention of preterm labor. Progesterones that can prevent preterm labor currently include: 17α-hydroxyprogesterone caproate, micronized progesterone capsules and gels. However, there is a lack of uniform standards in terms of indications, treatment time and dose of different drugs. 5. Conclusion After ovulation in normal women, the granulosa cells in the corpus luteum secrete progesterone, prompting the endometrium to change from the proliferative phase to the secretory phase and secrete various cytokines to adapt to the implantation of embryos. Since controlled ovarian stimulation is mostly used in the IVF-ET process, multiple follicles are induced to develop simultaneously to obtain multiple high-quality embryos to improve the cumulative clinical pregnancy rate. However, the simultaneous development of multiple follicles results in controlled ovarian stimulation cycles with serum levels of estrogen and progesterone much higher than physiological levels. It has been shown that high levels of estrogen and progesterone levels may affect endometrial tolerance. Luteal support is essential for endometrial tolerance, and the possible effects on endometrial tolerance should be taken into account when selecting the dose, timing and mode of administration of estrogen and progestin, and individualized dosing regimens should be developed.